Progress in physical activity and exercise and ...

PROGRESS IN PHYSICAL ACTIVITY AND EXERCISE AND AFFECTIVE AND ANXIETY DISORDERS: CURRENT VIEWS, PERSPECTIVES AND FUTURE DIRECTIONS Topic Editors Felipe Barreto Schuch, Neusa Rocha and Eduardo Lusa Cadore

PSYCHIATRY

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ISSN 1664-8714 978-2-88919-471-1 ISBN 978-2-88919-308-0 DOI 10.3389/978-2-88919-308-0 10.3389/978-2-88919-471-1

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January 2015 Progress in Physical activity and ExerciseNovember and Affective Anxiety Disorders | 1 2014and | Energy metabolism 1

PROGRESS IN PHYSICAL ACTIVITY AND EXERCISE AND AFFECTIVE AND ANXIETY DISORDERS: CURRENT VIEWS, PERSPECTIVES AND FUTURE DIRECTIONS Topic Editors: Felipe Barreto Schuch, Hospital de Clínicas de Porto Alegre, Brazil Neusa Rocha, Federal University of Rio Grande do Sul, Brazil Eduardo Lusa Cadore, Federal University of Rio Grande do Sul, Brazil

Physical activity and exercise were receiving a great attention as a strategy of prevention and treatment of affective and some anxiety disorders. Many studies have showed the efficacy of exercise in major depression and at depressed episode of bipolar patients, as well as, some authors shows the benefits of exercise in some anxiety disorders like Generalized Anxiety Disorder and Panic. Despite their efficacy, little is known concerning the main mechanisms related to the antidepressant and anxiolytic effects of exercise. Several studies in an animal model using Neurotrophic Factors, Oxidative Stress, Immunologic response and other biological markers reveal promising results. However, few studies were conducted in clinical samples. Additional to the antidepressant and anxiolytic effects, exercise appears improve QoL in major depressed, bipolar and anxiety patients. Theoretically, this increase may be associated with cognitive improvements, improvements at sleep quality, physical functioning, as well as other psychological issues as self-esteem, self-concept, and general well-being. The propose of this topic is to address the novelty and most recent research, related to antidepressant and anxiolytic effects of physical activity and exercise in patients with affective and anxiety disorders, as well as the issues associated with QoL improvement.The topic is looking for: – Clinical trials using exercise and physical activity as a treatment affective and anxiety disorders. – Studies investigating the optimal prescription factors (dose, volume, intensity, setting, frequency) associated with antidepressant and anxiolytic effects of physical activity and exercise for affective and anxiety disorder patients.

Frontiers in Psychiatry

January 2015 Progress in Physical activity and Exercise and Affective and Anxiety Disorders 2

– Original studies, comprehensive reviews, hypothesis and opinions concerning the mechanisms of antidepressant and anxiolytic effects of physical activity and exercise in affective and anxiety disorder patients. – Original studies, comprehensive reviews, hypothesis and opinions concerning other benefits of physical activity and exercise like : cognition, weight gain prevention and QoL in affective and anxiety disorder patients. – Translational research. – Studies of cost-efficacy analysis.



Table of Contents

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Progress in the study of the effects of exercise on affective and anxiety disorders Felipe Barreto Schuch Physical activity and exercise in the treatment of depression Holly Blake Treating depression and depression-like behavior with physical activity: an immune perspective Harris A. Eyre, Evan Papps and Bernhard T. Baune Recreational physical activity ameliorates some of the negative impact of major depression on health-related quality of life Scott B. Patten, Jeanne V. A. Williams, Dina H. Lavorato and Andrew G.M. Bulloch Is exercise an efficacious treatment for depression? A comment upon recent negative findings Felipe Barreto Schuch and Marcelo Pio de Almeida Fleck Effects of exercise and physical activity on anxiety Elizabeth Anderson and Geetha Shivakumar Meditative movement for depression and anxiety Peter Payne and Mardi A. Crane-Godreau Exercise interventions for the treatment of affective disorders – research to practice Robert Stanton, Brenda Happell, Melanie Hayman and Peter Reaburn Genetic modification of the effects of exercise behavior on mental health Nienke M. Schutte, Meike Bartels and Eco J. C. de Geus Exercise and mental health: what did we learn in the last 20 years? Andrea Camaz Deslandes Trophic mechanisms for exercise-induced stress resilience: potential role of interactions between BDNF and galanin Philip V. Holmes


EDITORIAL

PSYCHIATRY

published: 05 November 2014 doi: 10.3389/fpsyt.2014.00153

Progress in the study of the effects of exercise on affective and anxiety disorders Felipe Barreto Schuch* Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil *Correspondence: [email protected] Edited by: Ripu D. Jindal, University of Pittsburgh School of Medicine, USA Reviewed by: Nathalie Michels, Ghent University, Belgium Keywords: depression, anxiety, bipolar, quality of life, BDNF, galanin, meditative movement, genetic marker

Exercise has received great attention as a treatment for affective and anxiety disorders, and several studies have highlighted its mental and physical health benefits for these populations. Despite the innumerous benefits, however, there are many issues in the literature that need further exploration. In depression, exercise appears to moderately improve depressive symptoms. Blake (1) and Deslandes (2) reviewed the literature pointing to recent findings about the current use and efficacy of exercise in depression, and the challenges in treating depression with exercise. Some of these points, as the efficacy and effectiveness of exercise, and some potential factors related to its efficacy and effectiveness, were revisited in Schuch and Fleck (3). This paper highlighted the potential implications of the heterogeneity of depression diagnosis, the psychometric instruments, and other non-specific factors on the response rates found in clinical trials. In the same line, Stanton et al. (4) reviewed the effects of exercise, analyzing the guidelines that have discussed the prescription of exercise in major depression, bipolar disorder, and post-natal depression. Still related to prescription of exercise, Paine and Crane-Goodreau (5) reviewed studies using meditative movements on the treatment of depression and anxiety, suggesting its potential role in the treatment of depression and anxiety. Quality of life (QoL) improvement is a major challenge in the depression treatment. Reinforcing the discussion of Blake (1) regarding QoL, a longitudinal study enrolling more than 15,000 participants showed that recreational activity improved some of the negative impact of depression on health-related QoL (6). The mechanisms related to the antidepressant and anxiolytic effects of exercise remain unclear, though the literature reveals some insights in this regard. Anderson and Shivakumar (7) provided a review of the several potential physiological (hypothalamic–pituitary–adrenal axis, monoamines, opioids, and neurotrophic) and psychological (anxiety sensitivity and exposure, self-efficacy, and distraction) explanations to the anxiolytic effects of exercise. Similarly, Deslandes (2) discussed the potential role of brain-derived neurotrophic factor (BDNF) and neurogenesis in the antidepressant effects of exercise. Additionally, Holmes (8) analyzed the influence of Galanin and the interaction between Galanin and BDNF in the role of exercise-induced stress resilience. Genetic mechanisms, as pleiotropy, provide a possible explanation for some depressed populations’ lack of

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response to exercise, as well as the association between inactivity and depression (9). The neuroimmune system appears to be implicated in the pathophysiology of depression. Meanwhile, exercise has shown effects on several immunological biomarkers. In this regard, Eyre et al. (10) provide an extensive review regarding some specific factors such as changes on some factors as interleukins (1 and 6), macrophage migration inhibitory factor, central nervous system-specific autoreactive CD4+ T cells, M2 microglia, quiescent astrocytes, CX3CL1, and insulin-like growth 35 factor-1, Th1/Th2 balance, proinflammatory cytokines, C-reactive protein, M1 microglia, and reactive astrocytes. The topic presented several discussions regarding the current literature, the limitations of present studies, as well as several potential biological mediators of the relationship between exercise and depression/anxiety. The discussion may help researchers and other professionals of mental health form a broader comprehension of the exercise–depression relationship.

REFERENCES 1. Blake H. Physical activity and exercise in the treatment of depression. Front Psychiatry (2012) 3:106. doi:10.3389/fpsyt.2012.00106 2. Deslandes AC. Exercise and mental health: what did we learn in the last 20 years? Front Psychiatry (2014) 5:66. doi:10.3389/fpsyt.2014.00066 3. Schuch FB, de Almeida Fleck MP. Is exercise an efficacious treatment for depression? A comment upon recent negative findings. Front Psychiatry (2013) 4:20. doi:10.3389/fpsyt.2013.00020 4. Stanton R, Happell B, Hayman M, Reaburn P. Exercise interventions for the treatment of affective disorders – research to practice. Front Psychiatry (2014) 5:doi:10.3389/fpsyt.2014.00046 5. Payne P, Crane-Godreau MA. Meditative movement for depression and anxiety. Front Psychiatry (2013) 4:doi:10.3389/fpsyt.2013.00071 6. Patten SB, Williams JV, Lavorato DH, Bulloch AG. Recreational physical activity ameliorates some of the negative impact of major depression on health-related quality of life. Front Psychiatry (2013) 4:22. doi:10.3389/fpsyt.2013.00022 7. Anderson EH, Shivakumar G. Effects of exercise and physical activity on anxiety. Front Psychiatry (2013) 4:doi:10.3389/fpsyt.2013.00027 8. Holmes PV. Trophic mechanisms for exercise-induced stress resilience: potential role of interactions between BDNF and galanin. Front Psychiatry (2014) 5:doi:10.3389/fpsyt.2014.00090 9. Schutte NM, Bartels M, de Geus EJ. Genetic modification of the effects of exercise behavior on mental health. Front Psychiatry (2014) 5:doi:10.3389/fpsyt. 2014.00064 10. Eyre HA, Papps E, Baune BT. Treating depression and depression-like behaviour with physical activity: an immune perspective. Front Psychiatry (2013) 4:doi:10.3389/fpsyt.2013.00003

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Conflict of Interest Statement: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Advances in exercise and mood

Received: 28 July 2014; accepted: 20 October 2014; published online: 05 November 2014. Citation: Schuch FB (2014) Progress in the study of the effects of exercise on affective and anxiety disorders. Front. Psychiatry 5:153. doi: 10.3389/fpsyt.2014.00153

This article was submitted to Affective Disorders and Psychosomatic Research, a section of the journal Frontiers in Psychiatry. Copyright © 2014 Schuch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Frontiers in Psychiatry | Affective Disorders and Psychosomatic Research

November 2014 | Volume 5 | Article 153 | 6

OPINION ARTICLE

PSYCHIATRY

published: 07 December 2012 doi: 10.3389/fpsyt.2012.00106

Physical activity and exercise in the treatment of depression Holly Blake* Faculty of Medicine and Health Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, UK *Correspondence: [email protected] Edited by: Felipe Schuch, Hospital de Clinicas de Porto Alegre, Brazil Reviewed by: Felipe Schuch, Hospital de Clinicas de Porto Alegre, Brazil

Mental health problems continue to present a global challenge and contribute significantly to the global burden of human disease (DALYs). Depression is the most common psychiatric disorder and is thought to affect 121 million adults worldwide, and as such was rated as the fourth leading cause of disease burden in 2000 (Moussavi et al., 2007), projected to become the highest cause of disease burden by 2020. Antidepressant drugs are an effective and commonly used treatment for depression in primary care (Arroll et al., 2009), although almost half of those treated do not achieve full remission of their symptoms, and there remains a risk of residual symptoms, relapse/recurrence (Fava and Ruini, 2002). In those patients who do demonstrate improvements in depressive symptoms with antidepressant therapies, a time-lag in the onset of therapeutic effects is frequently reported. Antidepressant drugs are associated with adverse side effects (Agency for Health Research and Quality (AHRQ), 2012) and an increased risk of cardiovascular disease, particularly in those with pre-existing cardiovascular conditions or major cardiovascular risk factors (Waring, 2012). Furthermore, adherence to antidepressant medications is often poor and patients often prematurely discontinue their antidepressant therapy; it has been suggested that approximately 50% of psychiatric patients and 50% of primary care patients are non-adherent when assessed 6-months after the initiation of treatment (Sansone and Sansone, 2012). Psychological treatments for depression have been recommended in the UK National Institute for Health and Clinical Excellence (NICE) guidelines (NICE, 2009) and are becoming more commonplace for helping to reduce

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symptoms in depressed adults (Ambresin et al., 2012; Brakemeier and Frase, 2012), with even brief psychosocial interventions showing promise for improving adherence to depression medication treatment in primary care settings (Sirey et al., 2010). However, attendance at psychological intervention sessions can be poor since many depressed adults who may benefit from such treatments choose not to attend mental health clinics due to the perceived stigma of psychological therapies. As such there has been an increasing interest in the role of alternative interventions for depression. Physical exercise has been proposed as a complementary treatment which may help to improve residual symptoms of depression and prevent relapse (Trivedi et al., 2006). Exercise has been proposed by many as a potential treatment for depression and metaanalysis has demonstrated that effect sizes in intervention studies range from -0.80 to -1.1 (Rethorst et al., 2009). However, the evidence is not always consistent; recent research has shown that that provision of tailored advice and encouragement for physical activity did not improve depression outcome or antidepressant use in depressed adults when compared with usual care (Chalder et al., 2012). Other researchers have failed to find an antidepressant effect of exercise in patients with major depression but have found short term positive effects on physical outcomes, body composition and memory (Krogh et al., 2012). Others have argued that the nature of exercise delivery is an important factor, with exercise of preferred (rather than prescribed) intensity shown to improve psychological, physiological and social outcomes, and exercise participation rates in depressed individuals (Callaghan et al., 2011).

Research findings have been summarized by a recent Cochrane review which reported the findings of 32 randomized controlled trials in which exercise was compared to standard treatment, no treatment or a placebo treatment in adults (aged 18 and over) with depression (Rimer et al., 2012). This review concluded that exercise seems to improve depressive symptoms in people with a diagnosis of depression when compared with no treatment or control intervention, although highlighted that this should be interpreted with caution since the positive effects of exercise were smaller in methodologically robust trials. Similarly, a systematic review found that physical exercise programs obtain clinically relevant outcomes in the treatment of depressive symptoms in depressed older people (>60 years; Blake et al., 2009). Although the positive effects of exercise intervention on depressive symptoms are gaining more clarity, reviews suggest that there are currently insufficient high quality data to determine cost-benefit of exercise intervention in depression (Blake et al., 2009; Rimer et al., 2012). Many intervention studies with depressed populations are hampered by methodological weaknesses and small samples sizes. Further, comparisons between studies are often difficult due to variations in assessment or diagnosis of depression, level of severity of the condition, setting for delivery and size of the sample, outcomes of interest and the nature of the intervention delivered (type, frequency and duration of the intervention). Despite some inconsistencies in research findings, in the UK, the value of exercise continues to be substantiated by current reports and guidelines which include exercise as a management strategy

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for depression; NICE guidelines have recommended structured, supervised exercise programs, three times a week (45 min to 1 h) over 10–14 weeks, as a low-intensity Step 2 intervention for mild to moderate depression (NICE, 2009); Scottish Intercollegiate Guidelines Network (SIGN) for non-pharmaceutical management of depression in adults has recommended that structured exercise may be considered as a treatment option for patients with depression (SIGN, 2010); and exercise is specified as a treatment option for people with depression in a report for the National Service Framework for Mental Health (Donaghy and Durward, 2000). This is further substantiated by research which demonstrates that patients also find value in physical activity as an effective treatment for depression (Searle et al., 2011), although their perceptions of potential benefits and barriers to participation vary between individuals. The relationship between exercise and improved physical and psychological health is very well established in both healthy populations and also in people with long-term conditions, and active lifestyles are generally promoted in all populations where physical activity can be safely undertaken. Depression has been clearly associated with low levels of physical activity (Biddle, 2000; Goodwin, 2003) although this does not necessarily infer causality—there are many reasons why individuals who are depressed may have a more sedentary lifestyle, not least recognizing the effects of depression on motivation to engage in healthy lifestyle behaviors. We know that physical activity confers positive effects on mental well-being although the exact mechanisms which support this relationship are still poorly understood. Patients with depression have attributed this to a number of subjective benefits including biochemical pathways, and cognitive mechanisms include diversion from negative thinking, and a sense of purpose (Searle et al., 2011). Researchers have attempted to clarify this association and have identified a range of possible explanations. The potential role of the inflammatory response has been highlighted as a key mechanism in understanding the relationship between exercise

Physical activity and exercise in the treatment of depression

and mood (Hamer et al., 2012). It has also been proposed that physiological changes associated with exercise including endorphin and monoamine levels, or reduction in the levels of the stress hormone cortisol (Duclos et al., 2003) may exert an influence on mood. Further, a growing body of research on the role of neurogenesis in the etiology and treatment of depression has indicated that exercise may alter neurotransmitter function, and promote growth of the hippocampus which is known to be reduced in depressed populations (Lucassen et al., 2010). Indeed, laboratory studies have shown that the neurogenic response to exercise has been found to be much stronger than the response to antidepressant medications (Marlatt et al., 2010). Whilst researchers continue to investigate the mechanisms for this relationship the fact remains that physical activity is good for physical and mental health and therefore important for all. The social contact often derived from physical activity may play an important role in the relationship between physical activity or exercise and mood. Social support is known to be important for mental well-being, although early studies with older adults showed that exercise reduces depressive symptoms equally to social contact, with exercise also exerting a broader effect than social contact alone through reducing somatic symptoms (McNeil et al., 1991). Others have shown that physical activity intervention may improve mood and quality of life (QoL) equally to social contact in older adults, although this is yet to be tested in comparison with a “no-contact” control group (Kerse et al., 2010). The focus on the relationship between QoL and exercise is increasingly evident although there are few well-designed studies which have examined the relationship between physical exercise and QoL in depressed individuals. Improvements in global functionality, depressive and general psychopathological symptoms have been observed in depressed patients who have undertaken a supervised exercise regimen adjunctive to standard therapy with antidepressant drugs, with concomitant improvements in perceived QoL although only in the “physical domain” (Carta et al., 2008). Current trials are including QoL as


an important outcome variable in exercise interventions for patients with long-term conditions (e.g., Saxton et al., 2012). In fact, it has been argued that the promotion of exercise should now focus more heavily upon the benefits for QoL than focusing on the physical health benefits which have historically predominated in health promotion efforts (Stevens and Bryan, 2012). QoL is an important outcome criterion for interventions with depressed patients, particularly since patients with depressive disorders and/or depressive symptoms have been shown to have substantial and long-lasting decrements in multiple domains of functioning and well-being that equal or exceed those of patients with chronic medical illnesses (Hays et al., 1995). Definitions of QoL vary in the literature with some definitions focusing on individuals’ perceptions of their health status, whereas other definitions focus on individuals’ levels of satisfaction with their health status. However, a commonly cited definition is “a state of well-being that is a composite of two components: (1) the ability to perform everyday activities that reflect physical, psychological, and social well-being and (2) patient satisfaction with levels of functioning and the control of disease and/or treatmentrelated symptoms” (Gotay et al., 1992). Exercise has been associated with QoL in epidemiological studies, and regular exercise has shown to substantially improve QoL in populations with serious longterm conditions such as cancer (Burnham and Wilcox, 2002), Stroke (Smith and Thompson, 2008) and chronic obstructive pulmonary disease (Emery et al., 1998). However, there is less evidence for exercise improving QoL in disease-free populations. Although QoL has been advocated as either a primary or secondary outcome in health research (Speight and Barendse, 2010), a recent systematic review revealed that very few exercise and depression trials have actually included QoL as an outcome (Schuch et al., 2011). Largely due to the small number of intervention studies in this area, and methodological weaknesses within published studies, exercise intervention studies have not consistently demonstrated effects of exercise on QoL outcomes (Spirduso and Cronin, 2001; de Vreede et al., 2007), although in studies that do show positive


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effects, exercise dose has been found to be a significant predictor of change in mental and physical aspects of QoL (Martin et al., 2009). However, assessing QoL continues to be challenging, particularly in depressed populations where there may be an overlap in measurement between QoL and psychopathology; depression is known to negatively impact on different aspects of an individual’s life and this in turn can result in significant impairments in QoL (Ishak et al., 2012). The influence of depressive symptomatology on QoL scores may therefore invalidate research results (Aigner et al., 2006). Overall, the evidence suggests that exercise can improve depressive symptoms and this is observed even in those suffering from major depressive disorder (Pilu et al., 2007) who have been shown to benefit more from physical exercise than other psychiatric groups (Tordeurs et al., 2011). Exercise, additionally, may exert a positive influence on QoL, although these benefits are subjective in nature and measurement can be difficult due to methodological concerns. In practice, clinicians may be somewhat hesitant to recommend lifestyle changes to depressed patients since they may lack the motivation to exercise. This may be hampered further by public media coverage of negative trial findings which can amplify the difficulties in persuading patients with depression to take exercise (Trueland, 2012). However, the magnitude of the known health benefits of exercise for all mean that researchers have proposed this as a “first-line therapy” in all patients (Nahas and Sheikh, 2011) where prescription should be tailored to patients’ current level of activity, preferred type and intensity of activity.

REFERENCES Agency for Health Research and Quality (AHRQ). (2012). Medicine for Treating Depression: a Review of the Research for Adults. AHRQ Pub No. 12EHC012-A. Department of Health and Human Services, USA. Aigner, M., Förster-Streffleur, S., Prause, W., Freidl, M., Weiss, M., and Bach, M. (2006). What does the WHOQOL-Bref measure? Measurement overlap between quality of life and depressive symptomatology in chronic somatoform pain disorder. Soc. Psychiatry Psychiatr. Epidemiol. 41, 81–86. Ambresin, G., Despland, J. N., Preisig, M., and de Roten, Y. (2012). Efficacy of an adjunctive brief psychodynamic psychotherapy to usual inpatient treatment of depression: rationale and design of a randomized controlled

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trial. BMC Psychiatry 12:182. doi: 10.1186/ 1471-244X-12-182 Arroll, B., Elley, C. R., Fishman, T., Goodyear-Smith, F. A., Kenealy, T., Blashki, G., et al. (2009). Antidepressants versus placebo for depression in primary care. Cochrane Database Syst. Rev. 3:CD007954. doi: 10.1002/14651858.CD007954 Biddle, S. J. H. (2000). Emotion, Mood and Physical Activity. Physical Activity and Psychological Well-being. London: Routledge. Blake, H., Mo, P., Malik, S., and Thomas, S. (2009). How effective are physical activity interventions for alleviating depressive symptoms in older people? A systematic review. Clin. Rehabil. 23, 873–887. Brakemeier, E. L., and Frase, L. (2012). Interpersonal psychotherapy (IPT) in major depressive disorder. Eur. Arch. Psychiatry Clin. Neurosci. 262(Suppl. 2), 117–121. Burnham, T. R., and Wilcox, A. (2002). Effects of exercise on physiological and psychological variables in cancer survivors. Med. Sci. Sports Exerc. 34, 1863–1867. Callaghan, P., Khalil, E., Morres, I., and Carter, T. (2011). Pragmatic randomised controlled trial of preferred intensity exercise in women living with depression. BMC Public Health 11:465. doi: 10.1186/1471-2458-11-465 Carta, M. G., Hardoy, M. C., Pilu, A., Sorba, M., Floris, A. L., Mannu, F. A. et al. (2008). Improving physical quality of life with group physical activity in the adjunctive treatment of major depressive disorder. Clin. Pract. Epidemiol. Ment. Health 4, 1. Chalder, M., Wiles, N. J., Campbell, J., Hollinghurst, S. P., Haase, A. M., Taylor, A. H. et al. (2012). Facilitated physical activity as a treatment for depressed adults: randomised controlled trial. BMJ 344, e2758. de Vreede, P. L., van Meeteren, N. L., Samson, M. M., Wittink, H. M., Duursma, S. A., and Verhaar, H. J. (2007). The effect of functional tasks exercise and resistance exercise on health-related quality of life and physical activity. A randomised controlled trial. Gerontology 53, 12–20. Donaghy, M., and Durward, B. (2000). A Report on the Clinical Effectiveness of Physiotherapy in Mental Health. Research and Clinical Effectiveness Unit, Chartered Society of Physiotherapy. Duclos, M., Gouarne, C., and Bonnemaison, D. (2003). Acute and chronic effects of exercise on tissue sensitivity to glucocorticoids. J. Appl. Physiol. 94, 869–875. Emery, C. F., Schein, R. L., Hauck, E. R., and MacIntyre, N. R. (1998). Psychological and cognitive outcomes of a randomized trial of exercise among patients with chronic obstructive pulmonary disease. Health Psychol. 17, 232–240. Fava, G. A., and Ruini, C. (2002). Long-Term treatment of depression: there is more than drugs. Recenti Prog. Med. 93, 343–345. Goodwin, R. C. (2003). Association between physical activity and mental disorders among adults in the United States. Prev. Med. 36, 698–703. Gotay, C. C., Korn, E. L., McCabe, M. S., Moore, T. D., and Cheson, B. D. (1992). Quality-of-life assessment in cancer treatment protocols: research issues in protocol development. J. Natl. Cancer Inst. 84, 575–579.

Hamer, M., Endrighi, R., and Poole, L. (2012). Physical activity, stress reduction, and mood: insight into immunological mechanisms. Methods Mol. Biol. 934, 89–102. Hays, R. D., Wells, K. B., Sherbourne, C. D., Rogers, W., and Spritzer, K. (1995). Functioning and well-being outcomes of patients with depression compared with chronic general medical illnesses. Arch. Gen. Psychiatry 52, 11–19. Ishak, W. W., Balayan, K., Bresee, C., Greenberg, J. M., Fakhry, H., Christensen, S. et al. (2012). A descriptive analysis of quality of life using patientreported measures in major depressive disorder in a naturalistic outpatient setting. Qual. Life Res. doi: 10.1007/s11136-012-0187-6. [Epub ahead of print]. Kerse, N., Hayman, K. J., Moyes, S. A., Peri, K., Robinson, E., Dowell, A. et al. (2010). Home-based activity program for older people with depressive symptoms: DeLLITE–a randomized controlled trial. Ann. Fam. Med. 8, 214–223. Krogh, J., Videbech, P., Thomsen, C., Gluud, C., and Nordentoft, M. (2012). DEMO-II Trial. Aerobic exercise versus stretching exercise in patients with major depression-a randomised clinical trial. PLoS ONE 7:e48316. doi: 10.1371/ journal.pone.0048316 Lucassen, P. J., Meerlo, P., Naylor, A. S., van Dam, A. M., Dayer, A. G., Fuchs, E. et al. (2010). Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. Eur. Neuropsychopharmacol. 20, 1–17. Marlatt, M. W., Lucassen, P. J., and van Praag, H. (2010). Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice. Brain Res. 1341, 93–99. Martin, C. K., Church, T. S., Thompson, A. M., Earnest, C. P., and Blair, S. N. (2009). Exercise dose and quality of life: results of a randomized controlled trial. Arch. Intern. Med. 169, 269–278. McNeil, J. K., LeBlanc, E. M., and Joyner, M. (1991). The effect of exercise on depressive symptoms in the moderately depressed elderly. Psychol. Aging 6, 487–488. Moussavi, S., Chatterji, S., Verdes, E., Tandon, A., Patel, V., and Ustun, B. (2007). Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 370, 808–809. Nahas, R., and Sheikh, O. (2011). Complementary and alternative medicine for the treatment of major depressive disorder. Can. Fam. Physician 57, 659–663. National Institute for Health and Clinical Excellence. (2009). Depression: the Treatment and Management of Depression in Adults (Update). Available online at: http://www.nice.org.uk/guidance/CG90 Pilu, A., Sorba, M., Hardoy, M. C., Floris, A. L., Mannu, F. A., Seruis, M. L. et al. (2007). Efficacy of physical activity in the adjunctive treatment of major depressive disorders: preliminary results. Clin. Pract. Epidemiol. Ment. Health 3, 8. Rethorst, C. D., Wipfli, B. M., and Landers, D. M. (2009). The antidepressive effects of exercise: a meta-analysis of randomized trials. Sports Med. 39, 491–511. Rimer, J., Dwan, K., Lawlor, D. A., Greig, C. A., McMurdo, M., Morley, W. et al. (2012). Exercise


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for depression. Cochrane Database Syst. Rev. 7, CD004366. Sansone, R. A., and Sansone, L. A. (2012). Antidepressant adherence: are patients taking their medications? Innov. Clin. Neurosci. 9, 41–46. Saxton, J. M., Carter, A., Daley, A. J., Snowdon, N., Woodroofe, M. N., Petty, J. et al. (2012). Pragmatic exercise intervention for people with multiple sclerosis (ExIMS Trial): study protocol for a randomised controlled trial. Contemp. Clin. Trials pii: S1551-7144(12)00238-8. doi: 10.1016/j.cct.2012.10.011. [Epub ahead of print]. Schuch, F. B., Vasconcelos-Moreno, M. P., and Fleck, M. P. (2011). The impact of exercise on Quality of Life within exercise and depression trials: a systematic review. Ment. Health Phys. Act. 4, 43–48. Scottish Intercollegiate Guidelines Network. (2010). Non-pharmaceutical Management of Depression in Adults. Available online at: http://www.sign.ac.uk/pdf/sign114.pdf Searle, A., Calnan, M., Lewis, G., Campbell, J., Taylor, A., and Turner, K. (2011). Patients’ views of physical activity as treatment for depression: a qualitative study. Br. J. Gen. Pract. 61, 149–156.


Sirey, J. A., Bruce, M. L., and Kales, H. C. (2010). Improving antidepressant adherence and depression outcomes in primary care: the treatment initiation and participation (TIP) program. Am. J. Geriatr. Psychiatry 18, 554–562. Smith, P. S., and Thompson, M. (2008). Treadmill training post-stroke: are there any secondary benefits? A pilot study. Clin. Rehabil. 22, 997–1002. Speight, J., and Barendse, S. M. (2010). FDA guidance on patient reported outcomes. Br. Med. J. 340, c2921. Spirduso, W. W., and Cronin, D. L. (2001). Exercise dose-response effects on quality of life and independent living in older adults. Med. Sci. Sports Exerc. 33(Suppl. 6), S598–S608. discussion: S609–S610. Stevens, C. J., and Bryan, A. D. (2012). Rebranding Exercise: there’s an App for that. Am. J. Health Promot. 27, 69–70. Tordeurs, D., Janne, P., Appart, A., Zdanowicz, N., and Reynaert, C. (2011). [Effectiveness of physical exercise in psychiatry: a therapeutic approach?]. Encephale 37, 345–352. [Article in French].


Trivedi, M. H., Greer, T. L., Grannemann, B. D., Chambliss, H. O., and Jordan, A. N. (2006). Exercise as an augmentation strategy for treatment of major depression. J. Psychiatr. Pract. 12, 205–213. Trueland, J. (2012). Exercise caution. Nurs. Stand. 26, 24–25. Waring, W. S. (2012). Clinical use of antidepressant therapy and associated cardiovascular risk. Drug Healthc. Patient Saf. 4, 93–101. Received: 01 November 2012; accepted: 21 November 2012; published online: 07 December 2012. Citation: Blake H (2012) Physical activity and exercise in the treatment of depression. Front. Psychiatry 3:106. doi: 10.3389/fpsyt.2012.00106 This article was submitted to Frontiers in Affective Disorders and Psychosomatic Research, a specialty of Frontiers in Psychiatry. Copyright © 2012 Blake. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.


REVIEW ARTICLE

PSYCHIATRY

published: 04 February 2013 doi: 10.3389/fpsyt.2013.00003

Treating depression and depression-like behavior with physical activity: an immune perspective Harris A. Eyre 1,2 , Evan Papps 1 and Bernhard T. Baune 1 * 1 2

Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia

Edited by: Felipe Schuch, Hospital de Clínicas de Porto Alegre, Brazil Reviewed by: Oliver Grimm, Central Institute of Mental Health, Germany Mark Horowitz, King’s College London, UK Bianca W. De Aguiar, Universidade Federal do Rio Grande do Sul, Brazil *Correspondence: Bernhard T. Baune, Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia. e-mail: bernhard.baune@ adelaide.edu.au

The increasing burden of major depressive disorder makes the search for an extended understanding of etiology, and for the development of additional treatments highly significant. Biological factors may be useful biomarkers for treatment with physical activity (PA), and neurobiological effects of PA may herald new therapeutic development in the future. This paper provides a thorough and up-to-date review of studies examining the neuroimmunomodulatory effects of PA on the brain in depression and depression-like behaviors. From a neuroimmune perspective, evidence suggests PA does enhance the beneficial and reduce the detrimental effects of the neuroimmune system. PA appears to increase the following factors: interleukin (IL)-10, IL-6 (acutely), macrophage migration inhibitory factor, central nervous system-specific autoreactive CD4+ T cells, M2 microglia, quiescent astrocytes, CX3CL1, and insulin-like growth factor-1. On the other hand, PA appears to reduce detrimental neuroimmune factors such as: Th1/Th2 balance, pro-inflammatory cytokines, C-reactive protein, M1 microglia, and reactive astrocytes.The effect of other mechanisms is unknown, such as: CD4+CD25+ T regulatory cells (T regs), CD200, chemokines, miRNA, M2-type blood-derived macrophages, and tumor necrosis factor (TNF)-α [via receptor 2 (R2)]. The beneficial effects of PA are likely to occur centrally and peripherally (e.g., in visceral fat reduction). The investigation of the neuroimmune effects of PA on depression and depression-like behavior is a rapidly developing and important field. Keywords: physical activity, exercise, depression, psychiatry, immune, neurobiology

The increasing burden of major depressive disorder (MDD; WHO, 2008) makes the search for an extended understanding of etiology, and for the development of additional treatments highly significant. The global “pandemic” of physical inactivity (Lee et al., 2012) – a significant etiological factor for many noncommunicable diseases, including depression (Garber et al., 2011; Kohl et al., 2012; Lee et al., 2012) – as well as the growing evidence supporting the clinical utility of physical activity (PA) in many psychiatric disorders, make the biological effects of PA highly relevant (Knochel et al., 2012; Lautenschlager et al., 2012; Rimer et al., 2012). Biological factors may be useful biomarkers for treatment with PA, and neurobiological effects of PA may herald new therapeutic developments in the future. The neuroimmune system is important in the pathogenesis and pathophysiology of depression-like behaviors (Eyre and Baune, 2012c). Elevations in pro-inflammatory cytokines (PICs), causing neuroinflammation, are well known to be involved in the development of depression-like behaviors – e.g., sickness-like behavior, cognitive dysfunction, and anhedonia – in pre-clinical and clinical populations (Dantzer et al., 2008; McAfoose and Baune, 2009; Miller et al., 2009). The involvement of PICs in the development of depression-like behavior is often referred to as the cytokine model of depression (Dantzer et al., 2008; McAfoose and Baune, 2009; Miller et al., 2009).The neuroinflammatory state is associated with neurotransmitter dysfunction [e.g., reductions in serotonin

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(5-HT), as well as neurotoxic levels of glutamate (GLU) and tryptophan catabolites], reduced hippocampal (HC) neuroplasticity [e.g., neurogenesis, synaptic plasticity, and long-term potentiation (LTP)], oxidative stress, and glucocorticoid insensitivity (Dantzer et al., 2008; Miller et al., 2009; Eyre and Baune, 2012c; Leonard and Maes, 2012; Moylan et al., 2012). A variety of novel neuroimmune mechanisms may also be involved in the development of depression-like behaviors (Eyre and Baune, 2012c; Littrell, 2012). Cellular immune factors include various T cells [e.g., CD4+CD25+ T regulatory cells (T regs), CNS-specific autoreactive CD4+ T cells] and macrophages (e.g., M2-type blood-derived macrophages) involved in the model of protective immunosurveillance (Schwartz and Shechter, 2010a,b; Martino et al., 2011; Ron-Harel et al., 2011). These neuroprotective immune cells – found to release neurotrophic factors and antiinflammatory cytokines (AICs; Schwartz and Shechter, 2010a,b; Martino et al., 2011; Ron-Harel et al., 2011) – may be dysfunctional in the disease state (Schwartz and Shechter, 2010b). Moreover, the function of immunomodulatory proteins such as CX3CL1 (aka fractalkine; Rogers et al., 2011; Corona et al., 2012; Giunti et al., 2012), insulin-like growth factor-1 (IGF-1; Park et al., 2011a), and CD 200 (Lyons et al., 2007; Ojo et al., 2012) may be reduced. In clinical studies, PA has shown efficacy in the treatment of MDD (Rimer et al., 2012), schizophrenia (SCZ; Knochel et al., 2012), anxiety-based disorders (Asmundson et al., 2013), and in

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enhancing cognitive function in disorders of cognitive function (i.e.,Alzheimer’s disease,AD and mild cognitive impairment, MCI; Foster et al., 2011; Knochel et al., 2012; Lautenschlager et al., 2012). There are many reasons why PA is an attractive therapeutic option in psychiatry. It has a low side-effect profile and can be adapted according to a patient’s medical co-morbidities and functional status (Garber et al., 2011; Knochel et al., 2012; Rimer et al., 2012). PA also enhances self-esteem (Salmon, 2001), has less stigmatization than psychotherapy, may reduce the use of pharmacotherapies in MDD (Deslandes et al., 2010) and has a positive effect on cardiometabolic risk factors relevant to many psychiatric diseases (e.g., chronic inflammation, visceral fat mass, glucocorticoid sensitivity, glucose control, and insulin sensitivity; Gleeson et al., 2011; Baune et al., 2012c; Hamer et al., 2012; Knochel et al., 2012; Stuart and Baune, 2012). Physical activity has beneficial effects on depressive symptomatology in a variety of clinical contexts. It is found to have robust effects on the depressive phenotype found in MDD (Rimer et al., 2012), as well as beneficial effects on the depressive symptomatology involved in the negative symptoms of SCZ (Knochel et al., 2012). PA has also been shown to be effective in treating cognitive dysfunction-related depression (Knochel et al., 2012; i.e., in MCI and AD where a significant proportion of patients with AD suffer from co-morbid depression; Lee and Lyketsos, 2003). The clinical utility of PA in MDD is promising given most patients on antidepressants will not achieve remission following initial treatment (Trivedi et al., 2006), and nearly one-third will not achieve remission even following several treatment steps (Rush et al., 2006a,b). Encouragingly, a recent Cochrane meta-analysis of 28 trials (1101 participants) by Rimer et al. (2012) – comparing exercise with no treatment or control intervention – found a moderate clinical effect in MDD. Studies have found that whilst PA has an initial treatment effect equal to that of antidepressants (Rimer et al., 2012), its effects are slower (Blumenthal et al., 1999) with greater relapse prevention (Babyak et al., 2000). PA interventions have been shown to be efficacious as a stand-alone (Rethorst et al., 2009) and as an augmentation treatment for MDD (Trivedi et al., 2011). Adequate levels of PA are also found to have a role in the prevention of MDD (Pasco et al., 2011b). Physical activity interventions are found to have a multitude of effects on neuroimmune processes (Eyre and Baune, 2012a). Most notably PA interventions are found to reduce PIC levels in the brain of rodents (Eyre and Baune, 2012a) and in the periphery in clinical studies (Beavers et al., 2010a; Rethorst et al., 2012). The anti-inflammatory effects of PA may be related to acute elevations in neuroprotective interleukin-6 (IL-6; Funk et al., 2011), and resultant downstream changes, e.g., increased IL-1ra and reduced neuronal death in the HC (Funk et al., 2011). Reductions in pro-inflammatory visceral fat mass may also play a role in the anti-inflammatory effect of PA (Gleeson et al., 2011). The neuroimmune effects of PA were recently outlined in our review (Eyre and Baune, 2012a), however, there have been a large number of studies published in 2012 investigating other neuroimmune-related factors (Moon et al., 2012; Rethorst et al., 2012). Novel factors investigated include macrophage migration inhibitor factor (MIF; Moon et al., 2012), CX3CL1 (Vukovic et al., 2012), and IGF-1 (Duman et al., 2009). Taken together, there is a


Neuroimmune effects of physical activity

need for a review outlining and summarizing these recent studies in light of pre-existing literature with the intention of better understanding the neuroimmunological effects of PA. From this literature important questions arise: Are there PA types which are more effective than others? Are there subpopulations of patients with MDD who would benefit more from PA than antidepressants or psychotherapy? Can the neuroimmune effects of PA inform therapeutic development in the future? Are immune biomarkers potentially useful in measuring a treatment effect for PA in depression? This paper provides a thorough and up-to-date review of studies examining the neuroimmunomodulatory effects of PA on the brain in depression and depression-like behaviors.

METHODS This review utilized an electronic search of databases such as PubMed, PsychInfo, OvidSP, and Science Direct. An initial search was conducted using the following keywords: (PA OR exercise) AND (immune OR inflammation OR cytokine OR antiinflammatory OR immune cell OR glia OR neuroplasticity) AND/OR depression. Abstracts were selected based on the year of publication (between 1995 and December 2012), publication in the English language and of peer-reviewed type. They were excluded if they included anecdotal evidence. A total of 16,000 studies were found using these search terms. A total of 1000 articles remained after assessment of abstracts for relevance to the aims of this review. Of these, 770 studies were excluded after review of the full text if they did not examine the effect of the PA or depression on the immune system. A proportion of papers were found via the reference lists of the 1000 full text articles. Finally, 230 articles were utilized in this review.

CLINICAL EFFICACY OF PHYSICAL ACTIVITY IN DEPRESSION Evidence supporting the clinical efficacy of PA interventions with depression – and depression co-morbid with other diseases [MCI, coronary heart disease (CHD)] – is growing (Blumenthal et al., 2012a,b; Rimer et al., 2012). In the clinical setting, exercise interventions are defined as “planned, structured, and repetitive bodily movements done to improve or maintain one or more components of physical fitness” (Garber et al., 2011). Exercise types can include aerobic, resistance, neuromotor (involving balance, agility, and co-ordination), and flexibility types (Garber et al., 2011). The following section will outline clinical evidence supporting the use of exercise in depression. A 2012 re-analysis of available clinical trials by the Cochrane Group (Rimer et al., 2012; 2009 version; Mead et al., 2008) revealed 28 trials (1101 participants) comparing exercise with no treatment or control intervention finding a moderate clinical effect in MDD (standardized mean difference, SMD; −0.67 95% CI −0.90 to −0.43). However, when the meta-analysis was conducted with more strict criteria – i.e., studies with adequate allocation concealment, intention-to-treat analysis, and blinded outcome assessment – there were only four trials (326 participants), the SMD indicated a small clinical effect (SMD −0.31 95% CI −0.63 to 0.01). Moreover, data from the seven trials (373 participants) that provided long-term follow-up also found a small effect for exercise interventions (SMD −0.39, 95% CI −0.69 to −0.09).


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In comparison to cognitive behavioral therapy, six trials (152 participants) found no significant difference with exercise. Further investigating the individual clinical trials analyzed in this field yields interesting information on the clinical effect of exercise regimens. A 16-week randomized controlled trial (RCT) study by Blumenthal et al. (1999) found aerobic exercise and antidepressant (sertraline) treatment were equally effective in reducing depressive symptom severity [as per both Hamilton Depression Rating Scale (HAM-D) and Beck Depression Inventory (BDI)], however, sertaline had a faster initial response (in the first 3 weeks). Shortly after, a paper by Babyak et al. (2000) was published on the same study participants showing – at 6 months follow-up – patients assigned to the exercise program were less likely to relapse (no longer diagnostic for MDD or HAM-D < 8) than patients assigned to antidepressant treatment. Self-initiated exercise after the study intervention was associated with a reduced probability of depression at the end of the follow-up period (OR = 0.49). Treatment of depression in older people is often hampered by poor recognition and increased prevalence of medication sideeffects, polypharmacy, and poor adherence to treatment; therefore, exercise is increasingly being evaluated as a possible treatment. A recent meta-analysis (Bridle et al., 2012) of seven trials of subjects ≥60 years found exercise was associated with significantly lower depression severity (SMD −0.34; 95% CI −0.52 to −0.17). These findings were irrespective of whether participant eligibility was determined by clinical diagnosis or symptom checklist. An RCT in elderly patients (>60 years) with MDD – non-responders to escitalopram – found a 10-week Tai Chi Chih (TCC) exercise intervention augmented antidepressant treatment (Lavretsky et al., 2011). TCC exercise was chosen given it can be readily implemented among older adults with physical limitations (due to chronic medical illnesses or poor balance) and its added stress reduction and mindful cognitive properties. Multiple studies have shown regular, moderate PA can have a positive influence on depressive symptomatology in subjects with AD (Knochel et al., 2012), however Mahendra and Arkin (2003) found this beneficial effect was only significant after >1 year of PA. Deslandes et al. (2010) reported patients with co-morbid MCI and MDD could significantly reduce their antidepressant dose when they underwent a PA program. Exercise is shown to have some modest beneficial effects on certain aspects of neurocognitive disturbance in depression. An RCT study with patients who met MDD criteria found exercise (both supervised and home-based) performed better with exercise than sertraline on tests of executive functioning, but not on tests of verbal and working memory (Hoffman et al., 2008). A recent meta-analysis (Smith et al., 2010) examining the effects of aerobic exercise on neurocognitive performance found 29 studies (2049 participants) showing modest improvements in attention and processing speed (g = 0.158; 95% CI, 0.055–0.260), executive function (g = 0.123; 95% CI, 0.021–0.225), and memory (g = 0.128; 95% CI, 0.015–0.241). Depression is a common co-morbidity with a variety of cardiac conditions. Depression affects as many as 40% of patients with heart failure (HF), with up to 75% of patients reporting elevated depressive symptoms (Blumenthal et al., 2012a). For CHD, MDD affects 15–20% of cardiac patients and an additional 20% report elevated depressive symptoms (Blumenthal et al.,

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2012b). Blumenthal et al. (2012a) recently published an RCT of 2322 stable HF patients who underwent an aerobic exercise program (supervised for 1–3 months followed by home exercise for 9 months) or education and usual guideline-based HF care. Compared with usual care, aerobic exercise resulted in lower mean BDI-II scores at 3 and 12 months (differences of −0.76 and −0.68, respectively). Another study by Blumenthal et al. (2012b) assessed efficacy of 4 months of aerobic exercise and antidepressant treatments (sertraline) in reducing depressive symptoms and improving cardiovascular biomarkers in depressed patients with CHD. At 4 months, exercise and sertraline were equally as effective at reducing depressive symptoms (HRSD) vs. placebo. Exercise tended to result in greater reductions in heart rate variability vs. sertraline. When considering the anti-depressive effects of exercise – in addition to biological effects – we must consider psychosocial aspects. Studies have shown exercise regimens have a distraction effect (from negative thoughts and ruminations), provide a sense of mastery via the learning of new skills (Lepore, 1997), and hence enhance self-efficacy (Craft, 2005) and self-esteem (Salmon, 2001). A study by Craft (2005) found that those who experienced an increase in mood following exercise showed higher self-efficacy levels at 3 and 9 weeks post-exercise. Self-esteem is considered to be one of the strongest predictors of overall (Diener, 1984), subjective well-being and low self-esteem is considered to be closely related with mental illness (Fox, 2000). The abovementioned beneficial psychological effects may lead to the stress reducing and stressresilience enhancing effects of exercise (Salmon, 2001). Additionally, exercise regimens in a group setting may have a beneficial effect via training social skill deficits (Rimer et al., 2012).Therefore, considering the immunomodulatory effects of social support, i.e., social isolation stress is repeatedly shown to enhance inflammation in clinical and pre-clinical models (Hafner et al., 2011), the social interaction effects of PA interventions must be considered as a confounder. Whilst the vast majority of research using PA in psychiatry is positive and encouraging, it is important to also consider potential pre-cautions during PA interventions. Some studies report no effect for PA in depression (Rimer et al., 2012). This may be explained by inappropriate intensity of PA, or a too short duration of PA as a treatment (Rimer et al., 2012). In order to enhance the potential for antidepressant effects, multiple authors now recommend exercise of moderate-intensity and of at least 8 weeks duration (Mead et al., 2008; Trivedi et al., 2011; Rimer et al., 2012). PA regimens must be tailored according to the individual patient’s functional status and other co-morbidities. Failing to do so can lead to further morbidity and/or mortality. In patients with social phobia-related symptoms, the approach to PA interventions should be tailored appropriately.

NEUROIMMUNOLOGICAL EFFECTS OF PHYSICAL ACTIVITY IN DEPRESSION When considering the neuroimmunological effects of PA in depression, it is important to first outline the current understanding on neuroimmunological mechanisms of the depressionlike disease states. Therefore, the following section will outline these neuroimmunological mechanisms in detail; following, the neuroimmunological effects of PA will be examined.


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NEUROIMMUNOLOGICAL CHANGES IN DEPRESSION

The neuroimmunological changes found in depression involve humoral and cellular factors from both the innate and adaptive immune systems (Eyre and Baune, 2012c; Littrell, 2012). Humoral factors include PICs, AICs, C-reactive protein (CRP) as well as other immunomodulatory factors like CX3CL1, CD200, and IGF1 (Eyre and Baune, 2012b). Cellular factors include resident glia (e.g., astrocytes, microglia) and centrally migrating immune cells involved in protective immunosurveillance (e.g., CD4+ T cells and macrophages; Eyre and Baune, 2012b).


2012). An in-depth assessment on the effects of inflammation on these systems is outside the scope of this review and have been outlined recently (see Dantzer et al., 2008, 2011; McAfoose and Baune, 2009; Muller et al., 2011; Moylan et al., 2012). Rationale for examining immune mechanisms in addition to inflammation

Neuroinflammation and depression: a well recognized relationship

Whilst the cytokine and neuroinflammatory models of depression have been helpful in understanding the neurobiology behind the depressive phenotype, there are a number of clinical and biological reasons for investigating neuroimmune mechanisms in addition to inflammation. These factors include:

The neuroinflammatory state is well known to be associated with the depressive phenotype (Dantzer et al., 2008; Dowlati et al., 2010). For example, a recent meta-analysis found a significant correlation between tumor necrosis factor (TNF-α), IL-6, and CRP with depression in humans (Dowlati et al., 2010). Neuroinflammation is characterized by elevations in PICs and reductions in AICs and can arise within the CNS itself, or peripheral inflammatory signals can be transferred into the CNS (Dantzer et al., 2008; see Quan and Banks, 2007; for a review of peripheral-CNS pathways, including: the neural route, circumventricular organs, BBB transport of cytokines, and secretions from BBB cells). The neuroinflammatory state is known to cause neurovegetative or sickness-like symptoms, depression- and anxiety-like behaviors, as well as cognitive dysfunction and symptoms of Chronic Fatigue Syndrome (Dantzer et al., 2008; McAfoose and Baune, 2009; Dowlati et al., 2010; Miller, 2010; Yirmiya and Goshen, 2011; Bansal et al., 2012), and the causation of these phenotypic states by PICs has been modeled in both rodent and human models and extensively reviewed (Dantzer et al., 2008; Miller, 2010). Neuroinflammation-based models of depression have shown PICs to impact on other major neurobiological systems involved in depression. Neuroinflammation affects the neurotransmitter systems by activation if the tryphophan degrading enzyme, indoleamine 2,3 dioxygenase (IDO), altering metabolism of tryptophan into neurotoxic metabolites (3-hydroxykyurenin, 3-HK and quinolinic acid, QA) and depleting its availability for serotonin (5-HT) synthesis (Miller, 2010; Dantzer et al., 2011; Moylan et al., 2012). Inflammation also stimulates the reuptake of monoamines from the synapse by increasing the activity and the density of 5-HT, noradrenaline, and dopamine transporters (Moron et al., 2003; Nakajima et al., 2004; Zhu et al., 2006). Evidence suggests these immune mechanisms adversely affected glutamatergic neurotransmission causing GLU to rise to neurotoxic levels (McNally et al., 2008; Hashimoto, 2009; Popoli et al., 2012). In the neuroinflammatory state PICs may disrupt the capacity of the glucocorticoid receptor to translocate to the nucleus where it normally acts to suppress the activity of pro-inflammatory transcription factors such as nuclear factor-kappa B (NF-κB) – this is termed glucocorticoid resistance (Dantzer et al., 2008; Miller, 2010; Muller et al., 2011). High levels of PICs impair processes of neuroplasticity in the HC, such as neurogenesis, LTP, neurotrophin production (e.g., brain-derived neurotrophic factor, BDNF), and synaptic plasticity (Miller, 2010; Eyre and Baune, 2012c). In the context of reduced neuroplasticity, elevations in neurotoxic oxidative stress products and markers of apoptosis are found in the HC (Moylan et al.,

• A recent meta-analysis by Hannestad et al. (2011) found results arguing against the notion that resolution of a depressive episode is associated with normalization of levels of circulating PICs. This analysis of 22 studies (603 subjects) found – when all antidepressants were grouped – these medications reduced levels if IL-1β with a marginal effect on IL-6 (using less stringent fixed-effects models); there was no effect on TNF-α. However, a sub-group analysis of selective serotonin regulate inhibitors (SSRI) medication found a reduction in IL-6 and TNF-α. Other antidepressants did not reduce PIC levels. • Recent evidence has emerged to suggest no effect or even an antagonistic effect for anti-inflammatory medications in depression. A large-scale prospective cohort study of treatmentresistant depression, the “sequenced treatment alternatives to relieve depression” (STAR∗D), found an antagonistic effect for anti-inflammatory compounds on ADs (Warner-Schmidt et al., 2011). Patients reporting concomitant non-steroidal anti-inflammatory drug (NSAID) or other analgesic treatment showed a reduced therapeutic response to citalopram, hence, the authors suggest concomitant use of NSAIDs may be an important reason for high SSRI treatment resistance rates (WarnerSchmidt et al., 2011). A recent re-analysis reached a similar conclusion, with more modest effects persisting after adjustment for potential confounding variables (Gallagher et al., 2012). Another recently published study shows no difference between infliximab, a TNF-α antagonist, and placebo in a recent 12-week double-blind, placebo-controlled RCT for treatment-resistant depression (Raison et al., 2012). There was a significant effect for infliximab in individuals who had a high baseline hs-CRP (>5 mg/L) and a significant effect for placebo-treated patients at a baseline hs-CRP of 5.493 pg/ml) had a greater reduction in depressive symptoms (measured by IDS-C) than those with a low TNF-α level. Interestingly, this finding may suggest TNF-α as a moderator between SSRI and exercise treatment, and TNF-α levels could be used to recommend exercise rather than medication as part of a personalized treatment algorithm (Rethorst et al., 2012). This is given Eller et al. (2008) found high baseline TNF-α associated with non-response to an SSRI, and the Hannestad et al. (2011) meta-analysis also supports this association. There was a significant correlation between change in IL-1β and depression symptoms for the 16 KKW group, but not the 4 KKW group. The meta-analysis by Hannestad et al. (2011) also found a reduction in IL-1β correlated with better outcomes with SSRIs. Interestingly there was no change in cytokines levels following either exercise dosage. The authors suggest this may have occurred due to pre-treatment with SSRIs – a well known antiinflammatory agent (Hannestad et al., 2011) – which obscured the ability to detect changes in cytokine levels. Indeed, many past studies have shown exercise to have a robust anti-inflammatory effect in both human and rodent studies (Rethorst et al., 2011; Eyre and Baune, 2012a). Another recent study by Irwin and Olmstead (2012) utilized a 9-week TCC program in a healthy older adult population to investigate the effect of exercise on depression symptoms. This study


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FIGURE 1 | Depression-like behavior: balancing the beneficial and detrimental effects of the neuroimmune system. (A) This section shows the balance of the detrimental (red) and beneficial (green) effects of neuroimmune factors in the depressed state (i.e., detrimental factors out way beneficial factors). NB: depression-like behavior includes sickness-like behavior, anhedonia, anxiety-, and cognition-like behaviors. (B) This section shows a number of potential outcomes for the balance between the


abovementioned neuroimmune factors. (i) Shows a net detrimental effect which would lead to depression-like behaviors; clinically this could mean a depressive episode and could also increase relapse rates. (ii) Shows an equilibrium position which may suggest a stable/steady state in behavior; clinically this could mean a euthymic state. (iii) Shows a net beneficial effect which may attenuate depression-like behavior; clinically this could mean reduction or resolution of depressive symptoms and reduced relapse rates.

See Tables 1 and 2 for clinical studies examining the effects of exercise on neuroimmunological factors with and without depressive symptom correlations, respectively.

found TCC reduced depressive symptoms (BDI) in correlation with a reduction in IL-6 levels. TCC, however, had no effect on cellular markers of inflammation (i.e., sIL-1ra, sIL-6, sICAM, and IL-18). The authors suggest PA treatments may modulate IL-6 via decreasing sympathetic outflow. Aging and stress are associated with increases in circulating catecholamine levels, which are known to increase IL-6. A study by Kohut et al. (2006) found aerobic exercise reduced pro-inflammatory factors (i.e., CRP, IL-5, TNF-α, and IL-18) more than a combination of flexibility and strength exercise over a 10-month period. These exercise types both reduced depressive symptoms in the Geriatric Depression Scale (GDS). The robust lipolytic effects of PA are suggested to play a role in the antidepressant effects of PA in depression, via reducing the systemic pro-inflammatory state seen in obesity (Gleeson et al., 2011). A high visceral fat mass has been shown to cause a chronic inflammatory state, and this chronic inflammatory state may link depression and obesity (Stuart and Baune, 2012). Gleeson et al. (2011) also suggests physical inactivity is a risk factor for the accumulation of visceral fat which may predispose individuals to chronic illness like depression and heart disease via systemic PIC production by visceral fat mass.

As seen in Tables 3 and 4, there are a large number of studies investigating the neuroimmunological effects of PA. Studies have been variously conducted with and without behavioral correlates. The following section will summarize the salient studies in this field. A recent study found a voluntary exercise regimen to be associated with increased HC MIF, as well as Bdnf and Tph2 (tryphophan hydroxylase, involved in the synthesis of 5-HT) gene expression (Moon et al., 2012). These changes occurred in the context of reduced depression-like behavior (FST), and the effect of PA on these factors was mediated by the CD74-GTPase (MIF receptor) and RhoA-ERK1/2 pathway. MIF is a PIC expressed in the CNS whose deletion is associated with increased anxiety- and depression-like behaviors, as well as of impaired HC-dependent memory and HC neurogenesis (Conboy et al., 2011). Taken together, this information suggests a role of MIF in mediating the antidepressant action of exercise, probably by enhancing 5-HT neurotransmission and neurogenesis.



Neuroimmunological effects in pre-clinical populations

Eyre et al.

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Table 1 | Neuroimmune effects of physical activity in human populations with depressive symptom correlation. Study

Study objective

Study details

Exercise details

Neuropsychological

Immune testing

Results

ELISA of serum at

High baseline TNF-α

testing Rethorst

To examine the extent to which

Prospective. Randomized.

Randomized to

et al. (2012)

inflammatory markers can be used to

TREAD study

either 16 or 4

baseline and 12 weeks.

(>5.493 pg/ml) α greater ↓ in

KWW

IFN-γ, IL-1β, IL-6, and

depression sxs (IDS-C) over

TNF-α

12 weeks (p < 0.0001)

predict response to exercise treatment

Clinician: IDS-C30

after an incomplete response to an SSRI To examine how the inflammatory

Participants had MDD and

Aerobic EXC

Self-rated: IDS-SR30

Sig pos α between ∆ IL-1β and ∆

markers change with exercise and if those

were partial responders to

(treadmill or cycle

and HRSD-17

depression sxs (p = 0.04). For

changes are associated with dose of

an SSRI (i.e., ≥14 HRSD-17

ergometers)

exercise or changes in symptom severity

following >6 weeks but

16KKW not 4 KKW NS change in cytokine levels

15

modified Community

depressive symptoms was

Health Activities

moderated by PA (p = 0.02)

Model program

Among those who did not

for Seniors

engage in mod PA, higher

Activity

depressive sxs α ↑ IL-6 (r = 0.28,

Questionnaire for

p = 0.05)

older adults

Association was NS for moderate PA (r = −0.13, p = 0.38)

To evaluate the effects of a behavioral

83 healthy older adults

TCC and HE

BDI

ELISA of plasma for

High IL-6 at entry: TCC ↓ IL-6

Olmstead

intervention, TCC on circulating markers

(59–86 years)

Groups of 7–10

PSQI

IL-6, CRP, sIL-1ra, sIL-6,

comparable to those in TCC and

(2012)

of inflammation in older adults

RCT. Two arms – TCC, HE

TCC 20 min,

sICAM, IL-18

HE who had low IL-6 at entry

16 weeks

3/week

NB High

IL-6 in HE remained higher than

IL-6 > 2.46 pg/ml

TCC and HE with low entry IL-6

intervention + 9 weeks follow-up

TCC ns ∆ cellular markers of inflammation TCC = ↓ depressive sxs α ↓ IL-6 (Continued)



Irwin and

mechanisms

IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; ELISA, enzyme-linked immunosorbent assay; CRP, C-reactive protein; CES-D. Center for Epidemiologic Studies Depression Scale; NS, non-significant; TCC,

Tai Chi Chih.

10 months non-selective

factors and/or by β-adrenergic receptor

PSS, Perceived Stress Scale; CS, Coherence Scale; SPS, Social Previsions Scale; LOT, Life Orientation Test; α, association with or correlation with; EXC, exercise; IDS-C30, Inventory of Depressive Symptomatology;

45 min/day,

10 months

A sub-group of patients on

in part, by improvements in psychosocial

intervention among older adults would (2006)

TREAD, treatment with exercise augmentation for depression; KKW, kilocalories per kilogram of body weight per weeks; HE, health education; PSQI, Pittsburgh Sleep Quality Index; GDS, Geriatric Depression Scale;

β1β2-adrenergic antagonists antagonists were included

↓ CRP α ↓ depressive symptoms

No effect for non-selective

3 days/week,

β1β2-adrenergic

(FLEX) flexibility/strength EXC. and if this reduction would be mediated,

in IL-6, IL-18, CRP

strength EXC Randomized to aerobic or reduce serum inflammatory cytokines,

To determine if a long-term exercise Kohut et al.

IL-6, TNF-α, and IL-18

ELISA of plasma: CRP,

FLEX EXC = ↓ TNF-α, no change

CARDIO EXC = ↓ IL-6, IL-18, CRP,

TNF-α vs. FLEX

or flexibility/ Community-based

Immune testing testing

Neuropsychological Study objective Study

Table 1 | Continued

↑ optimism and LOT

Aerobic (CARDIO) Adults ≥ 64 years.

Results

EXC = ↓ depressive symptoms, GDS, PSS, CS, SPS,

Exercise details


Study details

Eyre et al.


Other studies found investigating the effects of PA on neuroimmune-related factors suggest PA increases antiinflammatory or immunomodulatory factors, e.g., IL-10, IGF-1, and CX3CL1. Sigwalt et al. (2011) shows that in a rat model of depression induced by repeated dexamethasone administration, swimming exercise reduces depression-like behavior in correlation with increased HC IL-10, BDNF, and DNA oxidation. Duman et al. (2009) and Kohman et al. (2012) show voluntary wheel running associated with increased IGF-1, a factor recently shown to have anti-inflammatory effects. Physical activity has been found to have beneficial effects on immunocompetent glial cells. A study by Latimer et al. (2011) has shown PA to revise age-related astrocyte hypertrophic/reactivity and myelin dysregulation – changes associated with neuroinflammation, cognitive decline, and reduced vascular function. Kohman et al. (2012) recently published a study showing PA attenuates aging associated increases in the proportion of new microglia within the HC (Iba-1 labeled). Furthermore, they show PA increases the pro-neurogenic phenotype of microglia (i.e., IGF-1-releasing microglia) which may contribute to increased HC neurogenesis. Given the robust anti-inflammatory effect of PA, the authors suggest PA may reduce PIC protein production leading to impaired microglial proliferation. A recent study by Barrientos et al. (2011) shows access to a running wheel reduced PIC expression from cultured microglia of aged rats. A recent study by Vukovic et al. (2012) suggests PA enhances the immunomodulatory factor CX3CL1 in the HC, with this associated with enhanced microglia-dependent neural precursor activity, as per the ex vivo neurosphere assay. A study by Funk et al. (2011) demonstrates that PA can offer significant protection to the HC in a chemical-induced injury model [via trimethyltin (TMT)] that involves TNF receptor signaling. PA attenuated TMT-induced changes such as loss of DG neurons and microglial activation. Furthermore, PA was accompanied by a significant elevation in IL-6 and IL-1ra mRNA levels and repressed elevations in PICs and chemokines (CCL2 and CCL3). Interestingly, the investigators identified a functional role for IL-6 in neuroprotection given mice deficient in IL-6 (IL-6 knock-out) were not responsive to the neuroprotective effects of PA on the HC. The effects of PA and TMT on IL-6 downstream signal events differed at the level of STAT3 activation. The beneficial effects of acute spikes in IL-6 with PA is clearly a significant factor in the anti-inflammatory effect of PA. In a human study by Starkie et al. (2003), 3 h of cycling blunted the endotoxin-induced increase in circulating TNF-α levels, and this effect was mimicked by an IL-6 infusion. Further, this regulatory role of IL-6 on TNF-α levels was demonstrated in anti-IL-6 treated mice and IL-6 knock-out mice (Mizuhara et al., 1994; Matthys et al., 1995). Whilst acute elevations in IL-6 are found throughout the body (Funk et al., 2011), a recent study shows a selective increase in IL-6 localized to the HC (Rasmussen et al., 2011). Neuroimmune cells may also have a role in the beneficial effects of PA. A study by Ziv et al. (2006) found PA, a component of the EE protocol, was associated with enhanced HC neurogenesis alongside a neuroprotective microglia phenotype and in the presence of a T-cell population. The role of CNS-specific T cells in the neuroprotective effects of PA is suggested given severe combined


Eyre et al.

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Table 2 | Neuroimmune effects of physical activity in human populations without depressive symptom correlation. Study

Study objective

Study details

Exercise details

Immune testing

Results

Nicklas et al.

To determine the effects of a long-term exercise

Single-blind, randomized,

Moderate-intensity PA.

ELISA of plasma: CRP

PA = ↓ IL-6 vs. SA. No

(2008)

intervention on two prominent biomarkers of

controlled trial

Combined aerobic, strength,

and IL-6

∆CRP

424 elderly (70–89 years),

balance, and flexibility exercise Approx 1 h sessions, 3/week.

non-disabled, and community-

Starting in center and transition

dwelling men and women

to home-based exercise

IL-6, CRP

RG and AG = ↓ CRP, no

Inflammation, CRP and IL-6, in elderly men and women

12 months of moderate-intensity PA vs. successful aging (SA) health education intervention Donges et al.

To determine the effects of 10 weeks of

(2010)

resistance or aerobic exercise training on IL-6

102 sedentary subjects Resistance group (RG), aerobic

Supervised exercise Control group maintained

and CRP. Further, to determine pre-training and

group (AG), or control. 10 weeks

sedentary lifestyle and dietary

effect on IL-6

patterns

post-training associations between alterations of IL-6 and CRP and alterations of total body fat

Subjects were involved in DEXA,

mass (TB-FM), intra-abdominal fat mass

muscle strength, aerobic fitness

(IA-FM), and total body lean mass (TB-LM)

measures, and lipid profiling

Martins et al.

Effect of exercise on metabolic profile in a

RCT

Aerobic: 40–80% HR max

Total cholesterol, triglyc-

Aerobic and resistance

(2010)

healthy elderly sample

N = 63

Resistance: 8

erides – colorimetric

exercise = improvement in

16 weeks

exercises – 1set/8reps to

end-point assay HDL, LDL – two-point

all measures

3sets/15reps

kinetic assay Hs-CRP – immunoturbidometry [@ baseline, 16 weeks] The purpose of this study was to examine the

29 younger (18–35 years) and 31

Inactive groups complete

(2007)

influence of a 12-week exercise training

old (65–85 years) subjects

12 weeks (3 days/week) of

no change for IL-6, IL-1β,

aerobic and resistance exc

TNF-α for both young and

program on inflammatory cytokine and CRP

ELISA of serum: CRP

concentrations. A secondary purpose was to

Assigned to young physically

Physically active control groups

ELISA of plasma: IL-6,

determine whether training-induced changes in

active, young physically inactive,

continue their normal exc

TNF-α, and IL-1β

cytokines and CRP were influenced by age

older physically active, older

programs

Prescribed EXC = ↓ CRP,

older subjects

physically inactive groups (Continued)



Stewart et al.

Eyre et al.


Table 2 | Continued Study

Study objective

Study details

Exercise details

Immune testing

Results

Black et al.

To examine if a yogic meditation might alter the

45 family dementia caregivers

8 weeks of KKM or RM. Both

Genome-wide

KKM = ↑ 19 gene’s

(2012)

activity of inflammatory and antiviral

Randomized to either Kirtan

12-min/day

transcriptional profiles

expression

transcription control pathways that shape

Kriya Meditation (KKM) or

collected from PBMC at

(immunoglobulin-related

immune cell gene expression

Relaxing Music (RM)

baseline and 8 weeks

transcripts)

follow-up. RNA

KKM = ↓ 49 gene’s

extraction ♦ cRNA

expression (PIC,

Transcript Origin

activation-related

Analysis

immediate-early genes). From plasmacytoid dendritic cells and B lymphocytes Effects may be due to ↓ NF-κB and IRF-1

Santos et al.

To assess the effects of moderate exercise

(2012)

training on sleep in elderly people as well as their cytokine profiles

22 male, sed, health, elderly

Mod training for 24 weeks.

ELISA plasma: TNF-α,

EXC = ↑ aerobic fitness, ↓

IL-6, IL-1, and IL-10

Polysomnography collected

60 min/day, 3 days/week Work rate equiv to ventilator

REM latency, ↓ time awake EXC = ↓ IL-6, TNF-α,

week – 1 and 6

aerobic threshold (VO2max , VATI)

TNF-α/IL-10

Total body mass and% fat.

EXC = ↑ IL-10

Whole-body plethysmography Cordova et al.

To investigate the association between

(2011)

long-term RT and circulating levels of the

Cross-sectional

In RT group women underwent


RT = ↓ IFN-γ, ↓ IL-6, ↓

8.6 ± 0.3 months of EXC.

IL-6, and IFN-γ

TNF-α vs. sed

pro-inflammatory mediators IL-6, TNF-α, and

54 years. Women

Mod-intensity (70% 1RM)

RT = ↓ caloric intake, sBP

IFN-γ in elderly women

RT – N = 28

50 min, 3/week, 3 sets of 12 reps

FFM 1/α IL-6

Sed – N = 26

per exercise

Libardi et al.

The aim of the present study was to evaluate

Healthy inactive subjects. ∼

3 weekly sessions for 60 min for


RT and CT = ↑ max

(2012)

the effects of 16 weeks of RT, ET, and CT on

49.5 years ± 5 Randomized to RT (N = 11), ET

16 weeks Max strength (1RM) tested in

IL-6, and CRP

strength ET and CT = ↑ VO2peak

(N = 12), CT (N = 11), or ctrl

bench press and leg press

inflammatory markers, CRP, and functional capacity in sedentary middle-age men February 2013 | Volume 4 | Article 3 | 24

BMI, waist-to-hip ration, DEXA

VO2peak measured in incremental

for FFM

exc test

Ns ∆ TNF-α, IL-6, CRP

Diet contents recorded Beavers et al.

Effect of chronic exercise on inflammation in the

RCT

12 months combined aerobics,

CRP, IL-6, IL-6sR, IL-8,

Exercise = ↓ IL-8, no ∆ in

(2010b)

elderly

N = 424

strength, flexibility/balance

and IL-15, Adiponectin,

others

training

Il-1rα, IL-2sRα, TNF-α, and sTNFRI and II ELISA (Continued)


(N = 13)

Eyre et al.

www.frontiersin.org Table 2 | Continued Study

Study objective

Colbert et al.

Effect of exercise on inflammation in the elderly

(2004)

Study details

Exercise details

Immune testing

Cross-sectional

Questionnaire

CRP, IL-6, and TNF-α

↑ Exercise α ↓ CRP

(blood/serum) – ELISA

(p < 0.01), ↓ IL-6

N = 3075

Results

(p < 0.001), ↓ TNF-α (p = 0.02) Geffken et al.

Effect of physical activity on inflammation in

Cross-sectional

(2001)

healthy elderly

N = 5201

Questionnaire

Nybo et al.

Is prolonged exercise associated with an altered

Quasi-experimental N = 8, young

2 min × 60 min bouts of cycle

(2002)

cerebral IL-6 response?

men Injected with radiotracer (133-Xe)

ergometer at 50% VO2max at

RCT N = 87 M34/F53

10 months: 45 min 3×/week

Blood: CRP, fibrinogen, Factor VIII activity, and

↑ Physical activity α ↓ Inflammatory markers

WCC

Kohut et al.

Effect of different exercise types on

(2006)

inflammation in the elderly Subset administered

Blood: IL-6 – ELISA

release

different temperatures Blood: CRP, IL-6, TNF-α,

Cardio = ↓ all markers

and IL-18

(p < 0.05)

Cardio: 65–80% VO2max

Strength/flex = ↓ TNF-α

Strength/flexibility: 10–15 reps

(p = 0.001) β-inhibitors made no effect

non-selective β-adrenergic antagonists

Prolonged exercise = ↑ IL-6

(moderate-intensity) Reuben et al.

Effect of physical activity on inflammation in

(2003)

elderly

Cross-sectional N = 877

Sef-reported: Yale Physical

Blood: IL-6,

↑ Physical activity α ↓ IL-6

activity survey

CRP – ELISA

and CRP

factor; IFN, interferon; ELISA, enzyme-linked immunosorbent assay; CRP, C-reactive protein.



RT, resistance training; ET, endurance training; CT, concurrent training; FFM, free fat mass; VATI, ventilator anaerobic threshold; TCC, Tai Chi Chih; RCT, randomized controlled trial; IL, interleukin; TNF, tumor necrosis

Study

Study objective

Animal

Moon et al.

To determine the underlying

Rat MIF−/− and

(2012)

mechanism of MIF in HC

WT

Exercise type

Voluntary EXC vs. ECT

Behavioral

Immune

assessment

measures

Results: behavioral

Results: neuroimmune

FST

In vivo: HC, RT-PCR,

MIF −/ − = depression-

EXC = ↑ Tph2 in vitro

IB, IHC

like

and in vivo (in vitro α ↑

In vitro: PCR, RT-PCR

behavior MIF −/ − = blunted

5-HT) EXC = ↑ Bdnf in vitro

antidepressant effect of

and in vivo

neurogenesis and its role in exercise-induced antidepressant

In vivo

28 days of EXC or 10 days of

therapy

component

ECT

Eyre et al.


Table 3 | Neuroimmunological effects of physical activity in rodent populations: with behavioral correlates.

EXC in FST ICV injection with MIF

Administration of MIF

CD 74-GPTase (MIF

In vitro: neuronal cell lines

protein =

receptor) and

treated with MIF. Neuro 2A

antidepressant effect in

RhoA-ERK1/2 pathway

FST

mediated MIF-induced Tph2 and Bdnf gene

MIF −/− = ↓ Dcx and Pax6

expression and 5-HT

siRNAs, GTPase RhoA

content

inhibitor CT04, MEK inhibitor

EXC = ↑ MIF (HC) (IHC

U0126

and IB)

Sigwalt

The aim of the present study was

Adult Wistar rats.

4 groups: CTRL, EXC, DEX,

et al. (2011)

to investigate the influence of

60 days Daily s.c.

and DEX + EXC

SPT

RIA blood

DEX: ↓ sucrose

corticosterone

consumption, ↑ immob

swimming exercise training on

dex (1.5 mg/kg) or

behavior and neurochemical

saline

corticosterone levels, ↓

parameters in a rat model of

administration

oxidation, ↑ IL-10, ↑

time

BDNF, ↓ blood adrenal weight, ↓ body

IHC HC: BDNF

EXC: ↑ sucrose

mass EXC: normalization of

8OHdG

consumption

BDNF and IL-10, ↑ blood

depression induced by repeated EXC: swimming/aerobic.

dexamethasone administration

FST

1 h/day, 5 days/week for

DEX: ↑ HC DNA

3 weeks. Overload of 5% of

testosterone, ↓ HC

rat body weight

DNA oxidation

CTRL: fluoxetine 10 mg/kg

RT-PCR HC: BDNF, IL-10

To assess the role of peripheral

et al. (2009)

IGF-I in mediating

Mice. C57Bl/6

Voluntary wheel running for

FST

PFC and HC

4 weeks

IGF-1 = ↓ immob time,

Anti-IGF-1 blocked the

↑ sucrose consumption

BDNF producing effect


antidepressant-like behavior

of EXC

under resting physiological conditions To investigate the extent to

uCMS

NIH

ELISA for IGF-1

which IGF-I might contribute to

Anti-IGF-1 blocked the

EXC = ↑ IGF-1 mRNA

antidepressant effect of

antidepressant-like behavior in

IGF-1 and

exercising mice

anti-IGF-1 was administered s.c.

SCT

ISH for IGF-1 and BDNF

EXC (FST)

EXC 6= PFC IGF-1 mRNA, nor HC and PFC BDNF

IHC, immunohistochemistry; IB, immunoblot; HC, hippocampus; PFC, pre-frontal cortex; SPT, sucrose preference test; dex, dexamethasone; FST, forced-swim test; MIF, macrophage migration inhibitory factor; RT-PCR, reverse transcription polymerase chain reaction; IB, immunoblot; ELISA, enzyme-linked immunosorbent assay; CTRL, control; BDNF, brain-derived neurotrophic factor; ISH, in situ hybridization.


Duman

Eyre et al.

www.frontiersin.org

Table 4 | Neuroimmune effects of physical activity in rodent populations: without behavioral correlates. Study

Study objective

Animal

Exercise Type

Neuroimmune measures

Funk et al.

To examine the impact of

Mice. Pathogen-free CD-1

Voluntary running wheel

Flow cytometry of CD11b, CD4,

EXC = ↓ neuronal death, TNF-α, TNFr1, MyD88,

(2011)

voluntary exercise on a model

access for 2 weeks

and GFP

TGF-β, CCL2, CCL3

IHC HC GFP+, Iba-1 cells; IL-6,

EXC = ↑ IL-1α mRNA, IL-1RA mRNA, IL-6 (mRNA

of TNF receptor activation

WT and IL-6−/−

dependent neuronal apoptosis

IP injection of TMT

Results: immune

IL-6 Rα, gp130, pAkt, p-STAT3

and protein), neuronal IL-6-Rα

Mass spect: Tin (sn)

TMT = ↑ IL-1α mRNA, IL-1RA mRNA, IL-6 (mRNA

(2.4 mg/kg) or saline

and protein), neuronal IL-6-Rα

Bone-marrow chimera

Fluorescent microscopy HC for

EXC = ↓ TNF-α cell death signaling pathways with

mice used to confirm lack

cell death and microglia

TMT. IL-6 pathway recruitment occurred in both

of infiltrating monocytes

phenotyping

EXC and TMT conditions – IL-6 downstream signal

qPCR

EXC 6= BDNF mRNA, NGF mRNA, GDNF mRNA

Microarray analysis: cell death

IL-6−/− mice: EXC showed ↓ neuroprotection

and IL-6 pathways

against TMT-induced injury

with TMT injury

events differed in the level of STAT3 activation

Kohman

To evaluate whether exercise

Adult (3.5 months) and

Vol running wheel for

IHC: BrdU HC

Aged mice = ↑ new microglia

et al. (2012)

modulates division and/or

aged (18 months) BALB/c

8 weeks

IF (confocal microscopy): HC:

EXC = ↓ new microglia in aged mice, ↑ microglial

activation state of microglia in

mice

microglia (Iba-1 +), microglial

IGF-1 expression, ↑ survival of new

the dentate gyrus of the

division (Iba-1+ and BrdU +),

neurons + proliferation

hippocampus

co-expression of IGF-1, new

EXC 6= microglial survival or proliferation in adult

neuron survival (BrdU × fraction

mice

displaying NeuN)

NB IGF-1-releasing

microglia considered

pro-neurogenic Yi et al.

To determine if regular

Ldlr−/− (low-density

Moderate, regular

IP glucose tolerance test

EXC = ↓ hypothalamic inflammation, ↓ microglial

(2012)

treadmill running may blunt

lipoprotein receptor

treadmill running exercise.

performed

activation

the effect of western diet on

deficiency) and WT mice

Involuntary. 30 min/day, Blood glucose levels measured Plasma insulin via ELISA Blood markers: TNF-α, IL-6, INF-g,

EXC = ↑ glucose tolerance EXC 6= circulating cytokines

hypothalamic inflammation

5 days/week, 26 weeks High-fat diet exposure Indirect calorimetry

Exhaustion tests at weeks 0 and 25


IL-1α, PAI-1, and MCP-1 IHC: hypothalamus for iba-1 Ehninger

Effect of exercise on cell

Female C57BL6/J mice, 2

Exercise vs. 2 sedentary

Iba-1, S100β, BrdU, NeuN, NG2,

Exercise and environmental enrichment = ↑

et al. (2011)

genesis in the adult amygdala

mo

controls (environmental

CNPase, GFAP, and ki67

oligodendroglial precursor proliferation, ↓

enrichment, standard

(hippocampus) – immunofluores-

microgliogenesis, ↑ neuroplasticity

housing) 10 days, voluntary

cence

wheel running (Continued)


performed

Eyre et al.



Study objective

Animal

Exercise Type


Results: immune

Latimer

To test the hypothesis that

C57BL/6 mice: young,

Voluntary exercise for

BP monitoring

EXC = ↓ HC GFAP and MBP which were

et al. (2011)

exercise initiated at mid-age

middle and aged

6 weeks

associated with aging

can slow the development of

IHC HC: astrocyte (GFAP) and

EXC = astrocytic changes, i.e., fewer branches,

hippocampal glial and vascular

myelin staining (MBP)

finer processes, less hypertrophied

biomarkers of early aging

ELISA HC: VEGF (angiogenesis

EXC = ↑ VEGF which was associated with aging

marker) Vascular casting: scanning

EXC = improved endothelial functioning (less

electron micrographs of MCA

ragged and irregular, ↑ ECN) and ↓ BP

were utilized Jeon et al.

To examine the effects of

C57BL/6 mice. Young

Forced treadmill exc for

Multiplexed bead-based

Treadmill EXC 6= ∆ serum cytokines/chemokines

(2012)

aging vs. exercise on serum

(2 months) and old

4 weeks. 30 min/day,

sandwich immunoassay of 50

significantly

profiles of cytokines and

(20 months)

5 days/week

serum cytokines/chemokines Older mice = ↑ eotaxin, IL-9, TARC vs. young mice

chemokines in mice models IL-1βXAT

Wu et al.

Effect of exercise on

Male/female

(2012)

hippocampal neurogenesis in

over-expression) C57BL/6

(IL-1β

infection

mice, 8–12 months vs. WT

Exercise vs. sedentary

MHCII DCX, BrdU, Iba-1

EXC 6= normalized neurogenesis in presence of

control Intra-hippocampal FIV

(HC) – immunohistochemistry

centrally mediated infection in IL-1β over-expression

EXC = ↓ TNF-α, IL-1β EXC = ↑ IFN-γ, CD11c, MHCII, CD40, MIP-1α

(feline immunodeficiency virus) injection vs. vehicle 2 weeks, voluntary wheel running Nichol et al.

Effect of exercise on amyloid

Male/female Tg2576


(2008)

load and neuroinflammation

C57B16/SJL mice,

control 3 weeks, voluntary

HC and cortex Pro-inflammatory: IL-1β,

in AD mice

16–18 months vs. WT

wheel running

TNF-α – ELISA Adaptive/alternate immune

EXC = ↑ CD68, mannose receptor

markers: IFN-γ, CD40, February 2013 | Volume 4 | Article 3 | 28

CD11c,

(↑ Perivascular MΦ infiltrate)

MIP-1α – Immunohistochemistry Aβ – ELISA, Dot-blot analysis CD68, mannose receptor – Immunohistochemistry Iba-1 – Western blot (Continued)


MHCII – Western blot

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Study objective

Animal

Exercise Type


Results: immune

Vukovic

Effect of exercise on

Female TG-Csf1r-GFP


HC BrdU, DCX,

EXC = microglial-dependent ↑ neural precursor

et al. (2012)

microglial-dependent

C57BL/6J mice, 6–8-week

control Ex vivo

Iba-1 – immunostaining

activity

hippocampal neurogenesis

old

neurospehere culture

CX3CL1 – ELISA MHCII – FACS

EXC = ↓ MHCII+ve microglia, EXC = ↑ CX3CL1 (neuroprotective phenotype)

with/without microglia 2 weeks, voluntary wheel running Ziv et al.

Role of immune cells in

Male Sprague Dawley rats,

(2006)

neurogenesis

12-week old

EE vs. standard lab control Healthy rats vs.

From HC: IHC: BrdU, MHCII,

EE = ↑ neurogenesis and adaptive microglial profile

IB-4, IGF-1, NeuN, BDNF, and

in presence of function T-cell population

immune-deficient (SCID

TCR

mice) Leem et al.

Effect of exercise in

Male/Female Tg-Ad

(2011)

neuroinflammation in AD

(NSE/htau23) C57BL/6

EXC vs. sedentary control Intermediate (12 m/min)

mice

mice 16 months vs. WT

vs. high intensity exercise (19 m/min)

From HC RT-PCR: TNF-α, IL-6, and IL-1β WB: iNOS, ERK, COX-2, p38 IHC: phosphoTau, GFAP, MAC-1,

High intensity EXC = ↓ phsophoTau (p < 0.05) High intensity EXC = ↓ gliosis [MAC-1, GFAP] (p < 005) High intensity EXC = ↓ µAPK-dependent signaling pathway [↓ iNOS, TNF-α, IL-6, IL-1β] (p < 0.05)

and p65 Herring

Effect of exercise in

Female Tg-AD APP695


From entire brain, except,

EXC = ↓ Aβ in offspring via altered APP processing

et al. (2012)

pregnancy on AD pathology in

CRND8 x

control

offspring

C57BL/6-C3H-HeJ vs. WT

Duration of pregnancy,

cerebellum, brainstem IHC: Aβ, A1F1, laminin, RELN

(p < 0.022) EXC = ↑ angiogenesis (p < 0.022)

RT-PCR: Gapdh, APP, Lpap1,

EXC = ↑ neuroplasticity

voluntary wheel running

ApoE1, Clu, A2m, Mmp9, Mme DC protein assay: Aβ40 , Aβ42 ,

EXC = ↓ microgliosis (p = 0.002), pro-inflammatory

sAPPα

mediators, oxidative stress mediators (p = 0.029)

WB: APP, CTFβ, RELn, APOER2, VLDR, ADC, CYP, IDE, IBA-1, PTGER2, SOD1, SOD2 Role of brain MΦ on central

Male C57Bl/6 mice,


et al. (2010)

cytokines and fatigue

8-week old

control MΦ depletion with

post-exercise

IL-1β (cerebrum) – ELISA

EXC = ↑ IL-1β from MΦs

clodronate injection or saline Single bout of exercise, 22 m/min for 150 m ECN, endothelial cell nuclei; EE, environmental enrichment; IHC, immunohistochemistry; WB, western blot; TCR, T-cell receptor; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; ELISA, enzyme-linked immunosorbent assay; CRP, C-reactive protein; EXC, exercise; APP, amyloid precursor protein; TMT, trimethyltin; NGF, nerve growth factor, BDNF, brain-derived neurotrophic factor; VEGF, vascular endothelial growth factor.



Carmichael

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immunodeficiency (SCID) mice exposed to EE did not show an increase in neurogenesis.

MODEL OF NEUROIMMUNOLOGICAL EFFECTS OF PA IN DEPRESSION Emerging evidence suggests the neuroimmune system is critical in both the development of depression-related pathophysiology and in the treatment of depression. From the evidence available in this field, PA has a multitude of beneficial neuroimmune effects which may lead to the improvement of depression-related neurobiological processes, hence leading to reduced depression-like behaviors. From a neuroimmune perspective, evidence suggests PA does enhance the beneficial and reduce the detrimental effects of the neuroimmune system. Figure 2 outlines these effects. PA appears to increase the following factors: IL-10, IL-6 (acutely), MIF, CNSspecific autoreactive CD4+ T cells, M2 microglia, quiescent astrocytes, CX3CL1, and IGF-1. On the other hand, PA appears to reduce detrimental neuroimmune factors such as: Th1/Th2 balance, PICs, CRP, M1 microglia, and reactive astrocytes. The effect of other factors is unknown, such as: T regs, CD200, chemokines, miRNA, M2-type blood-derived macrophages, and TNF-α (via R2). The beneficial effects of PA are likely to occur centrally and peripherally (e.g., in visceral fat reduction). Based on the strong relationship between the neuroimmune system and other neurobiological systems (i.e., neuroplasticity,

FIGURE 2 | Physical activity in depression: antidepressant via enhancing the beneficial effects of the neuroimmune system. This figure illustrates the effects of PA on the brain as per the balance between beneficial and detrimental effects of neuroimmune factors. PA appears to enhance the beneficial effects of the neuroimmune



neuroendocrine function, and neurotransmission), we believe PA may exert beneficial behavioral effects via these neurobiological systems. PA’s neuroimmune effects are likely involved in enhanced neuroplasticity, reduced oxidative stress, increases in 5HT, dopamine, and noradrenaline, and enhanced glucocorticoid sensitivity. The neurobiological effects of PA – mediated largely via the neuroimmune system – are likely involved with reduced depression-like behaviors in rodents (i.e., sickness-like behavior, anhedonia, anxiety-, and cognition-like behaviors) and positive clinical effects (i.e., reduced depressive symptoms, enhanced cognitive function, relapse reduction, and early intervention).

DISCUSSION Physical activity is increasingly investigated as a preventative, early intervention, and treatment option in depression. The interest in investigation of PA may have arisen for a number of reasons: the burden of depression is rising so novel therapeutic and preventative options are required (WHO, 2008; Berk and Jacka, 2012; Cuijpers et al., 2012; Southwick and Charney, 2012). Rates of physical inactivity are high and rising in modern society (Lee et al., 2012) with early evidence suggesting a link to the development of depression (Pasco et al., 2011a,b). Pharmacotherapy in depression is hampered by relatively high rates of resistance (Rush et al., 2006a,b) and considerable side-effects. Evidence is emerging to suggest co-morbid links between obesity, diabetes,

system and reduce the detrimental effects. From a behavioral perspective, this may lead to reduced depression-like behaviors. From a clinical perspective, this may lead to reduced depressive symptoms, depressive episode resolution, and reduced relapse rates (disease prevention).


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heart disease, and depression (Baune and Thome, 2011; Stuart and Baune, 2012), and PA is a therapeutic option with beneficial cardio-metabolic effects (Gleeson et al., 2011; Baune et al., 2012c; Hamer et al., 2012; Knochel et al., 2012; Stuart and Baune, 2012). Based on the abovementioned factors, research has been reviewed to better understand the clinical efficacy of different types of PA, to understand the mechanism of action of PA and to investigate for suitable biomarkers to measure the treatment effect of PA in depression. Further, a model has been suggested in order to assist in understanding the neuroimmune effects of PA in depression. An important consideration in the field of exercise immunology includes understanding the mechanisms of treatment response in depression vs. other psychiatric disorders. At present the authors feel there is no enough data to address this issue systematically, with research evidence. Whilst it would appear that the effects of PA on the immune system in various disorders – in both clinical and pre-clinical studies – is quite similar, i.e., PICs are reduced (particularly in anxiety disorders and depression; Gleeson et al., 2011; Eyre and Baune, 2012a), this considers only a narrow range of neuroimmune factors. The authors speculate that the therapeutic difference in PA may occur due to subtle variations in the neuroimmune and neurobiological effect, dependent upon the CNS environment with each pathophysiological state. Studies investigating the effects of a standardized exposure to PA, in various psychiatric disorders in parallel, may assist in unraveling this complex issue. When considering the balance between the beneficial and detrimental effects of immune system and the effect of PA tipping this balance toward beneficial effects, it is important to consider: Is it possible to restore the balance of the immune system and still suffer from a low mood? This is an interesting question and open to debate. It would seem that the majority of evidence suggests that as inflammation increases, mood worsens, and as inflammation reduces, mood appears to return to normal. For example, this is shown in meta-analysis by Dowlati et al. (2010) and a review by Maes (2011) whereby depressive symptoms are associated with elevations in PIC levels. Another meta-analysis shows inflammation reduces with the use of SSRIs in the treatment of depression (Hannestad et al., 2011). However, there are other therapies such as SNRIs which appear to improve mood, yet have no effect on levels of inflammation (Hannestad et al., 2011). Therefore, more work is required to understand the effect of various therapies (pharmacological and non-pharmacological) on a wider variety of immune-related factors such as cytokines (anti- and pro-inflammatory), anti-inflammatory factors like IGF-1, CD200, CX3CL1, MIF, neuroprotective systemic immune cells, etc. Interestingly, Walker (2012) suggests the concentration of antidepressant drug molecules in the CNS also alters the immunomodulatory effects. FUTURE DIRECTIONS

From current evidence, it is not possible to ascertain the type of PA which is most efficacious in the treatment of depression. Although, most evidence surrounds aerobic exercise. We suggest the need for

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head-to-head clinical trials comparing different types and intensities of PA to assist in making this issue clearer. Moreover, when considering the effects of distinct types of PA on neuroimmune factors, we also suggest the need for more head-to-head clinical trials (Baune and Eyre, 2012). The most recent study examining the effects of PA on depressive symptoms was conducted by Rethorst et al. This study suggests that a high baseline TNF-α level was associated with a greater reduction in depressive symptomatology as opposed a high baseline TNF-α level being a negative factor for SSRI efficacy (Hannestad et al., 2011; Rethorst et al., 2012). The authors suggest TNF-α levels may be a moderator between SSRI and exercise treatment, and may have a role in personalized treatment algorithms. Whilst this is a promising suggestion, further research is needed to replicate these findings. Our understanding of the neuroimmune effects of PA in depression will continue to develop as the understanding of the neuroimmune effects of PA develop. It is important to consider the use of multi-biomarker methods within this area in order to better understand potential biomarkers. For example, the use of neuroimaging, serum protein and genetic markers, and behavioral analysis. This type of methodology is increasingly employed in biological psychiatry (Baune et al., 2010, 2012a,b). There are a number of neuroimmune-related factors which are yet to be considered in the effect of PA in depression. These factors include micro ribonucleic acid (miRNA), neuroimmune-related Positron Emission Tomography (PET) ligands, the neuroprotective effects of neuroimmune factors, and immune cells. Evidence is emerging to suggest a role for miRNAs, factors involved in regulating gene expression at the post-translational level, in modulating the effects of the immune system (Ponomarev et al., 2012). For example, various miRNAs such as miR-155 and miR-124 may have a role in polarizing microglia toward pro- or anti-inflammatory phenotypes, respectively (Ponomarev et al., 2012). The PET ligand, Translocator Protein (TPSO) ligand [(11)C]PBR28, a marker of microglial activation, was recently found to be elevated by LPSinduced systemic inflammation in non-human primates (Hannestad et al., 2012). This ligand has the potential to be utilized as a biomarker to investigate if activation of microglia may be a mechanism through which systemic inflammatory processes influence the disease course of depression. The biology of centrally migrating immune cells and CNS immune cells in depression is complex and far from understood. Regarding the debated issue of blood-derived macrophages can enter the brain parenchyma: research and development into novel methods for permanent differential labeling of circulating monocytes, as contrasted with resident microglia, is underway (Prinz et al., 2011). Studies are required to better understand the role of protective immunosurveillance in clinical and rodent models of depression.

CONCLUSION The investigation of the neuroimmune effects of PA on depression and depression-like behavior is a rapidly developing and important field. This paper summarizes the most recent findings in the area and proposes a model whereby PA enhances the beneficial effects of the neuroimmune system and reduces the detrimental effects of the neuroimmune system.


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REFERENCES Aarum, J., Sandberg, K., Haeberlein, S. L., and Persson, M. A. (2003). Migration and differentiation of neural precursor cells can be directed by microglia. Proc. Natl. Acad. Sci. U.S.A. 100, 15983–15988. Anisman, H., Ravindran, A. V., Griffiths, J., and Merali, Z. (1999). Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features. Mol. Psychiatry 4, 182–188. Araque, A., Parpura, V., Sanzgiri, R. P., and Haydon, P. G. (1999). Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215. Asmundson, G. J. G., Fetzner, M. G., DeBoer, L. B., Powers, M. B., Otto, M. W., and Smits, J. A. J. (2013). Let’s get physical: a contemporary review of the anxiolytic effects of exercise for anxiety and its disorders. Depress. Anxiety. doi: 10.1002/da.22043. [Epub ahead of print]. Babyak, M., Blumenthal, J. A., Herman, S., Khatri, P., Doraiswamy, M., Moore, K., et al. (2000). Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom. Med. 62, 633–638. Bachstetter, A. D., Morganti, J. M., Jernberg, J., Schlunk, A., Mitchell, S. H., Brewster, K. W., et al. (2011). Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol. Aging 32, 2030–2044. Bansal, A. S., Bradley, A. S., Bishop, K. N., Kiani-Alikhan, S., and Ford, B. (2012). Chronic fatigue syndrome, the immune system and viral infection. Brain Behav. Immun. 26, 24–31. Barrientos, R. M., Frank, M. G., Crysdale, N. Y., Chapman, T. R., Ahrendsen, J. T., Day, H. E., et al. (2011). Little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes. J. Neurosci. 31, 11578–11586. Battista, D., Ferrari, C. C., Gage, F. H., and Pitossi, F. J. (2006). Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus. Eur. J. Neurosci. 23, 83–93. Baune, B. T., Dannlowski, U., Domschke, K., Janssen, D. G., Jordan, M. A., Ohrmann, P., et al. (2010). The interleukin 1 beta (IL1B) gene is associated with failure to achieve remission and impaired emotion processing in major


depression. Biol. Psychiatry 67, 543–549. Baune, B. T., and Eyre, H. (2012). Novel perspectives on the role of immune biomarkers in exercise and depression. Brain Behav. Immun. 26, 512. Baune, B. T., Konrad, C., Grotegerd, D., Suslow, T., Birosova, E., Ohrmann, P., et al. (2012a). Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain. J. Neuroinflammation 9, 125. Baune, B. T., Konrad, C., Grotegerd, D., Suslow, T., Ohrmann, P., Bauer, J., et al. (2012b). Tumor necrosis factor gene variation predicts hippocampus volume in healthy individuals. Biol. Psychiatry 72, 655–662. Baune, B. T., Stuart, M., Gilmour, A., Wersching, H., Heindel, W., Arolt, V., et al. (2012c). The relationship between subtypes of depression and cardiovascular disease: a systematic review of biological models. Transl. Psychiatry 2, e92. Baune, B. T., Ponath, G., Rothermundt, M., Riess, O., Funke, H., and Berger, K. (2008a). Association between genetic variants of IL-1beta, IL-6 and TNF-alpha cytokines and cognitive performance in the elderly general population of the MEMOstudy. Psychoneuroendocrinology 33, 68–76. Baune, B. T., Wiede, F., Braun, A., Golledge, J., Arolt, V., and Koerner, H. (2008b). Cognitive dysfunction in mice deficient for TNF and its receptors. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 1056–1064. Baune, B. T., and Thome, J. (2011). Translational research approach to biological and modifiable risk factors of psychosis and affective disorders. World J. Biol. Psychiatry 12(Suppl 1), 28–34. Beavers, K. M., Brinkley, T. E., and Nicklas, B. J. (2010a). Effect of exercise training on chronic inflammation. Clin. Chim. Acta 411, 785–793. Beavers, K. M., Hsu, F. C., Isom, S., Kritchevsky, S. B., Church, T., Goodpaster, B., et al. (2010b). Long-term physical activity and inflammatory biomarkers in older adults. Med. Sci. Sports Exerc. 42, 2189–2196. Beers, D. R., Henkel, J. S., Zhao, W., Wang, J., and Appel, S. H. (2008). CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc. Natl. Acad. Sci. U.S.A. 105, 15558–15563. Ben Menachem-Zidon, O., Avital, A., Ben-Menahem, Y., Goshen, I., Kreisel, T., Shmueli, E. M., et al. (2011). Astrocytes support


hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling. Brain Behav. Immun. 25, 1008–1016. Berk, M., and Jacka, F. (2012). Preventive strategies in depression: gathering evidence for risk factors and potential interventions. Br. J. Psychiatry 201, 339–341. Beumer, W., Gibney, S. M., Drexhage, R. C., Pont-Lezica, L., Doorduin, J., Klein, H. C., et al. (2012). The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J. Leukoc. Biol. 92, 959–975. Bilbo, S. D., Smith, S. H., and Schwarz, J. M. (2012). A lifespan approach to neuroinflammatory and cognitive disorders: a critical role for glia. J. Neuroimmune Pharmacol. 7, 24–41. Black, D. S., Cole, S. W., Irwin, M. R., Breen, E., St Cyr, N. M., Nazarian, N., et al. (2012). Yogic meditation reverses NF-kappaB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. Psychoneuroendocrinology. doi: 10.1016/j.psyneuen.2012.06.011. [Epub ahead of print]. Blume, J., Douglas, S. D., and Evans, D. L. (2011). Immune suppression and immune activation in depression. Brain Behav. Immun. 25, 221–229. Blumenthal, J. A., Babyak, M. A., Moore, K. A., Craighead, W. E., Herman, S., Khatri, P., et al. (1999). Effects of exercise training on older patients with major depression. Arch. Intern. Med. 159, 2349–2356. Blumenthal, J. A., Babyak, M. A., O’Connor, C., Keteyian, S., Landzberg, J., Howlett, J., et al. (2012a). Effects of exercise training on depressive symptoms in patients with chronic heart failure: the HF-action randomized trial. JAMA 308, 465–474. Blumenthal, J. A., Sherwood, A., Babyak, M. A., Watkins, L. L., Smith, P. J., Hoffman, B. M., et al. (2012b). Exercise and pharmacological treatment of depressive symptoms in patients with coronary heart disease: results from the UPBEAT (understanding the prognostic benefits of exercise and antidepressant therapy) Study. J. Am. Coll. Cardiol. 60, 1053–1063. Bluthe, R. M., Castanon, N., Pousset, F., Bristow, A., Ball, C., Lestage, J., et al. (1999). Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats. Psychoneuroendocrinology 24, 301–311. Bowen, K. K., Dempsey, R. J., and Vemuganti, R. (2011). Adult interleukin-6 knockout mice show compromised

neurogenesis. Neuroreport 22, 126–130. Bracchi-Ricard, V., Brambilla, R., Levenson, J., Hu, W. H., Bramwell, A., Sweatt, J. D., et al. (2008). Astroglial nuclear factor-kappaB regulates learning and memory and synaptic plasticity in female mice. J. Neurochem. 104, 611–623. Bridle, C., Spanjers, K., Patel, S., Atherton, N. M., and Lamb, S. E. (2012). Effect of exercise on depression severity in older people: systematic review and meta-analysis of randomised controlled trials. Br. J. Psychiatry 201, 180–185. Brynskikh, A., Warren, T., Zhu, J., and Kipnis, J. (2008). Adaptive immunity affects learning behavior in mice. Brain Behav. Immun. 22, 861–869. Butovsky, O., Koronyo-Hamaoui, M., Kunis, G., Ophir, E., Landa, G., Cohen, H., et al. (2006a). Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc. Natl. Acad. Sci. U.S.A. 103, 11784–11789. Butovsky, O., Ziv, Y., Schwartz, A., Landa, G., Talpalar, A. E., Pluchino, S., et al. (2006b). Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 31, 149–160. Butovsky, O., Kunis, G., KoronyoHamaoui, M., and Schwartz, M. (2007). Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer’s disease model. Eur. J. Neurosci. 26, 413–416. Butovsky, O., Talpalar, A. E., BenYaakov, K., and Schwartz, M. (2005). Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol. Cell. Neurosci. 29, 381–393. Butti, E., Bergami, A., Recchia, A., Brambilla, E., Del Carro, U., Amadio, S., et al. (2008). IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis. Gene Ther. 15, 504–515. Capuron, L., and Miller, A. H. (2011). Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol. Ther. 130, 226–238. Cardon, M., Ron-Harel, N., Cohen, H., Lewitus, G. M., and Schwartz, M. (2010). Dysregulation of kisspeptin and neurogenesis at adolescence


Eyre et al.

link inborn immune deficits to the late onset of abnormal sensorimotor gating in congenital psychological disorders. Mol. Psychiatry 15, 415–425. Carlson, N. G., Wieggel, W. A., Chen, J., Bacchi, A., Rogers, S. W., and Gahring, L. C. (1999). Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. J. Immunol. 163, 3963–3968. Carmichael, M. D., Davis, J. M., Murphy, E. A., Carson, J. A., Van Rooijen, N., Mayer, E., et al. (2010). Role of brain macrophages on IL-1beta and fatigue following eccentric exercise-induced muscle damage. Brain Behav. Immun. 24, 564–568. Chapoval, S., Dasgupta, P., Dorsey, N. J., and Keegan, A. D. (2010). Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6. J. Leukoc. Biol. 87, 1011–1018. Chiu, I. M., Chen, A., Zheng, Y., Kosaras, B., Tsiftsoglou, S. A., Vartanian, T. K., et al. (2008). T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc. Natl. Acad. Sci. U.S.A. 105, 17913–17918. Cohen, H., Ziv, Y., Cardon, M., Kaplan, Z., Matar, M. A., Gidron, Y., et al. (2006). Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells. J. Neurobiol. 66, 552–563. Colbert, L. H., Visser, M., Simonsick, E. M., Tracy, R. P., Newman, A. B., Kritchevsky, S. B., et al. (2004). Physical activity, exercise, and inflammatory markers in older adults: findings from the Health, Aging and Body Composition Study. J. Am. Geriatr. Soc. 52, 1098–1104. Conboy, L., Varea, E., Castro, J. E., Sakouhi-Ouertatani, H., Calandra, T., Lashuel, H. A., et al. (2011). Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memoryrelated behaviors. Mol. Psychiatry 16, 533–547. Cordova, C., Lopes, E. S. F. Jr., Pires, A. S., Souza, V. C., Brito, C. J., Moraes, C. F., et al. (2011). Longterm resistance training is associated with reduced circulating levels of IL6, IFN-gamma and TNF-alpha in elderly women. Neuroimmunomodulation 18, 165–170.

www.frontiersin.org


Corona, A. W., Huang, Y., O’Connor, J. C., Dantzer, R., Kelley, K. W., Popovich, P. G., et al. (2010). Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide. J. Neuroinflammation 7, 93. Corona, A. W., Norden, D. M., Skendelas, J. P., Huang, Y., O’Connor, J. C., Lawson, M., et al. (2012). Indoleamine 2,3dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX(3)CR1)deficient mice. Brain Behav Immun. doi:10.1016/j.bbi.2012.08.008. [Epub ahead of print]. Costello, D. A., Lyons, A., Denieffe, S., Browne, T. C., Cox, F. F., and Lynch, M. A. (2011). Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice: a role for Toll-like receptor activation. J. Biol. Chem. 286, 34722–34732. Cox, F. F., Carney, D., Miller, A. M., and Lynch, M. A. (2012). CD200 fusion protein decreases microglial activation in the hippocampus of aged rats. Brain Behav. Immun. 26, 789–796. Craft, L. (2005). Exercise and clinical depression: examining two psychological mechanisms. Psychol. Sport. Exerc. 6, 151–171. Cuijpers, P., Beekman, A. T., and Reynolds, C. F. III. (2012). Preventing depression: a global priority. JAMA 307, 1033–1034. Curtsinger, J. M., Schmidt, C. S., Mondino, A., Lins, D. C., Kedl, R. M., Jenkins, M. K., et al. (1999). Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. J. Immunol. 162, 3256–3262. Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W., and Kelley, K. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56. Dantzer, R., O’Connor, J. C., Lawson, M. A., and Kelley, K. W. (2011). Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 36, 426–436. Derecki, N. C., Cardani, A. N., Yang, C. H., Quinnies, K. M., Crihfield, A., Lynch, K. R., et al. (2010). Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080. Derecki, N. C., Quinnies, K. M., and Kipnis, J. (2011). Alternatively

activated myeloid (M2) cells enhance cognitive function in immune compromised mice. Brain Behav. Immun. 25, 379–385. Deslandes, A. C., Moraes, H., Alves, H., Pompeu, F. A., Silveira, H., Mouta, R., et al. (2010). Effect of aerobic training on EEG alpha asymmetry and depressive symptoms in the elderly: a 1-year follow-up study. Braz. J. Med. Biol. Res. 43, 585–592. Dhabhar, F. S., Burke, H. M., Epel, E. S., Mellon, S. H., Rosser, R., Reus, V. I., et al. (2009). Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression. J. Psychiatr. Res. 43, 962–969. Diener, E. (1984). Subjective well-being. Psychol. Bull. 94, 542–575. Donges, C. E., Duffield, R., and Drinkwater, E. J. (2010). Effects of resistance or aerobic exercise training on interleukin-6, C-reactive protein, and body composition. Med. Sci. Sports Exerc. 42, 304–313. Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E. K., et al. (2010). A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457. Duman, C. H., Schlesinger, L., Terwilliger, R., Russell, D. S., Newton, S. S., and Duman, R. S. (2009). Peripheral insulin-like growth factor-I produces antidepressant-like behavior and contributes to the effect of exercise. Behav. Brain Res. 198, 366–371. Ehninger, D., Wang, L. P., Klempin, F., Romer, B., Kettenmann, H., and Kempermann, G. (2011). Enriched environment and physical activity reduce microglia and influence the fate of NG2 cells in the amygdala of adult mice. Cell Tissue Res. 345, 69–86. Ekdahl, C. T. (2012). Microglial activation – tuning and pruning adult neurogenesis. Front. Pharmacol. 3:41. doi:10.3389/fphar.2012.00041 Eller, T.,Vasar,V., Shlik, J., and Maron, E. (2008). Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 445–450. Erickson, K. I., Miller, D. L., and Roecklein, K. A. (2012). The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist 18, 82–97. Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., et al. (2011). Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. U.S.A. 108, 3017–3022.

Eyre, H., and Baune, B. T. (2012a). Neuroimmunological effects of physical exercise in depression. Brain Behav. Immun. 26, 251–266. Eyre, H., and Baune, B. T. (2012b). Neuroimmunomodulation in unipolar depression: a focus on chronobiology and chronotherapeutics. J. Neural Transm. 119, 1147–1166. Eyre, H., and Baune, B. T. (2012c). Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology 37, 1397–1416. Foster, P. P., Rosenblatt, K. P., and Kuljis, R. O. (2011). Exercise-induced cognitive plasticity, implications for mild cognitive impairment and Alzheimer’s disease. Front. Neurol. 2:28. doi:10.3389/fneur.2011.00028 Fox, K. (2000). “The effects of exercise on self-perceptions and selfesteem,” in Physical Activity and Psychological Well-Being, ed. F. K. Biddle Sjh (London: Routledge), 88–117. Frank, M. G., Baratta, M. V., Sprunger, D. B., Watkins, L. R., and Maier, S. F. (2007). Microglia serve as a neuroimmune substrate for stressinduced potentiation of CNS proinflammatory cytokine responses. Brain Behav. Immun. 21, 47–59. Fujio, K., Okamura, T., and Yamamoto, K. (2010). The Family of IL10-secreting CD4+ T cells. Adv. Immunol. 105, 99–130. Funk, J. A., Gohlke, J., Kraft, A. D., McPherson, C. A., Collins, J. B., and Jean Harry, G. (2011). Voluntary exercise protects hippocampal neurons from trimethyltin injury: possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity. Brain Behav. Immun. 25, 1063–1077. Gallagher, P. J., Castro,V., Fava, M.,Weilburg, J. B., Murphy, S. N., Gainer, V. S., et al. (2012). Antidepressant response in patients with major depression exposed to NSAIDs: a pharmacovigilance study. Am. J. Psychiatry 169, 1065–1072. Garber, C. E., Blissmer, B., Deschenes, M. R., Franklin, B. A., Lamonte, M. J., Lee, I. M., et al. (2011). American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med. Sci. Sports Exerc. 43, 1334–1359. Garg, S. K., Banerjee, R., and Kipnis, J. (2008). Neuroprotective immunity: T cell-derived glutamate endows astrocytes with a neuroprotective


Eyre et al.

phenotype. J. Immunol. 180, 3866–3873. Geffken, D. F., Cushman, M., Burke, G. L., Polak, J. F., Sakkinen, P. A., and Tracy, R. P. (2001). Association between physical activity and markers of inflammation in a healthy elderly population. Am. J. Epidemiol. 153, 242–250. Giunti, D., Parodi, B., Usai, C., Vergani, L., Casazza, S., Bruzzone, S., et al. (2012). Mesenchymal stem cells shape microglia effector functions through the release of CX3CL1. Stem Cells 30, 2044–2053. Gleeson, M., Bishop, N. C., Stensel, D. J., Lindley, M. R., Mastana, S. S., and Nimmo, M. A. (2011). The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615. Godbout, K., Fenn, A., Huang, Y., and Gensel, J. (2012). Central interleukin-4 infusion after a peripheral lipopolysaccharide injection promotes a neuroprotective CNS environment with increased M2 microglia. Brain Behav. Immun. 26, S29–S30. Hafner, S., Emeny, R. T., Lacruz, M. E., Baumert, J., Herder, C., Koenig, W., et al. (2011). Association between social isolation and inflammatory markers in depressed and nondepressed individuals: results from the MONICA/KORA study. Brain Behav. Immun. 25, 1701–1707. Hamer, M., Sabia, S., Batty, G. D., Shipley, M. J., Tabak, A. G., SinghManoux, A., et al. (2012). Physical activity and inflammatory markers over 10 years: follow-up in men and women from the Whitehall II Cohort Study. Circulation 126, 928–933. Hannestad, J., Dellagioia, N., and Bloch, M. (2011). The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36, 2452–2459. Hannestad, J., Gallezot, J. D., Schafbauer, T., Lim, K., Kloczynski, T., Morris, E. D., et al. (2012). Endotoxin-induced systemic inflammation activates microglia: [(1)(1)C]PBR28 positron emission tomography in nonhuman primates. Neuroimage 63, 232–239. Hashimoto, K. (2009). Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res. Rev. 61, 105–123. Hauben, E., Butovsky, O., Nevo, U., Yoles, E., Moalem, G., Agranov, E., et al. (2000). Passive or active


immunization with myelin basic protein promotes recovery from spinal cord contusion. J. Neurosci. 20, 6421–6430. Hein, A. M., and O’Banion, M. K. (2012). Neuroinflammation and cognitive dysfunction in chronic disease and aging. J. Neuroimmune Pharmacol. 7, 3–6. Herring, A., Donath, A., Yarmolenko, M., Uslar, E., Conzen, C., Kanakis, D., et al. (2012). Exercise during pregnancy mitigates Alzheimerlike pathology in mouse offspring. FASEB J. 26, 117–128. Himmerich, H., Milenovic, S., Fulda, S., Plumakers, B., Sheldrick, A. J., Michel, T. M., et al. (2010). Regulatory T cells increased while IL1beta decreased during antidepressant therapy. J. Psychiatr. Res. 44, 1052–1057. Hinwood, M., Morandini, J., Day, T. A., and Walker, F. R. (2012). Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the Medial prefrontal cortex. Cereb. Cortex 22, 1442–1454. Hoffman, B. M., Blumenthal, J. A., Babyak, M. A., Smith, P. J., Rogers, S. D., Doraiswamy, P. M., et al. (2008). Exercise fails to improve neurocognition in depressed middle-aged and older adults. Med. Sci. Sports Exerc. 40, 1344–1352. Irwin, M. R., and Olmstead, R. (2012). Mitigating cellular inflammation in older adults: a randomized controlled trial of Tai Chi Chih. Am. J. Geriatr. Psychiatry 20, 764–772. Jenkins, M. K., and Johnson, J. G. (1993). Molecules involved in T-cell costimulation. Curr. Opin. Immunol. 5, 361–367. Jeon, H., Mun, G. I., and Boo, Y. C. (2012). Analysis of serum cytokine/chemokine profiles affected by aging and exercise in mice. Cytokine 60, 487–492. Kaneko, M., Stellwagen, D., Malenka, R. C., and Stryker, M. P. (2008). Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex. Neuron 58, 673–680. Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., and Walters, E. E. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602. Kim, S. J., Lee, H., Joung, H. Y., Lee, G., Lee, H. J., Shin, M. K., et al. (2011). T-bet deficient mice exhibit


resistance to stress-induced development of depression-like behaviors. J. Neuroimmunol. 240–241, 45–51. Kim, S. J., Lee, H., Lee, G., Oh, S. J., Shin, M. K., Shim, I., et al. (2012). CD4+CD25+ regulatory T cell depletion modulates anxiety and depression-like behaviors in mice. PLoS ONE 7:e42054. doi:10.1371/journal.pone.0042054 Kipnis, J., Avidan, H., Caspi, R. R., and Schwartz, M. (2004a). Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia. Proc. Natl. Acad. Sci. U.S.A. 101(Suppl 2), 14663–14669. Kipnis, J., Cohen, H., Cardon, M., Ziv, Y., and Schwartz, M. (2004b). T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Natl. Acad. Sci. U.S.A. 101, 8180–8185. Kipnis, J., Derecki, N. C., Yang, C., and Scrable, H. (2008). Immunity and cognition: what do agerelated dementia, HIV-dementia and ‘chemo-brain’ have in common? Trends Immunol. 29, 455–463. Knochel, C., Oertel-Knochel, V., O’Dwyer, L., Prvulovic, D., Alves, G., Kollmann, B., et al. (2012). Cognitive and behavioural effects of physical exercise in psychiatric patients. Prog. Neurobiol. 96, 46–68. Kohl, H. W. III, Craig, C. L., Lambert, E. V., Inoue, S., Alkandari, J. R., Leetongin, G., et al. (2012). The pandemic of physical inactivity: global action for public health. Lancet 380, 294–305. Kohm, A. P., McMahon, J. S., Podojil, J. R., Begolka, W. S., Degutes, M., Kasprowicz, D. J., et al. (2006). Cutting edge: anti-CD25 monoclonal antibody injection results in the functional inactivation, not depletion, of CD4+CD25+ T regulatory cells. J. Immunol. 176, 3301–3305. Kohman, R. A., Deyoung, E. K., Bhattacharya, T. K., Peterson, L. N., and Rhodes, J. S. (2012). Wheel running attenuates microglia proliferation and increases expression of a proneurogenic phenotype in the hippocampus of aged mice. Brain Behav. Immun. 26, 803–810. Kohut, M. L., McCann, D. A., Russell, D. W., Konopka, D. N., Cunnick, J. E., Franke, W. D., et al. (2006). Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of betablockers, BMI, and psychosocial factors in older adults. Brain Behav. Immun. 20, 201–209.

Kokaia, Z., Martino, G., Schwartz, M., and Lindvall, O. (2012). Crosstalk between neural stem cells and immune cells: the key to better brain repair? Nat. Neurosci. 15, 1078–1087. Koronyo-Hamaoui, M., Ko, M. K., Koronyo, Y., Azoulay, D., Seksenyan, A., Kunis, G., et al. (2009). Attenuation of AD-like neuropathology by harnessing peripheral immune cells: local elevation of IL-10 and MMP-9. J. Neurochem. 111, 1409–1424. Latimer, C. S., Searcy, J. L., Bridges, M. T., Brewer, L. D., Popovic, J., Blalock, E. M., et al. (2011). Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice. PLoS ONE 6:e26812. doi:10.1371/journal.pone.0026812 Lautenschlager, N. T., Cox, K., and Cyarto, E. V. (2012). The influence of exercise on brain aging and dementia. Biochim. Biophys. Acta 1822, 474–481. Lavretsky, H., Alstein, L. L., Olmstead, R. E., Ercoli, L. M., Riparetti-Brown, M., Cyr, N. S., et al. (2011). Complementary use of Tai Chi Chih augments escitalopram treatment of geriatric depression: a randomized controlled trial. Am. J. Geriatr. Psychiatry 19, 839–850. Lee, H. B., and Lyketsos, C. G. (2003). Depression in Alzheimer’s disease: heterogeneity and related issues. Biol. Psychiatry 54, 353–362. Lee, I. M., Shiroma, E. J., Lobelo, F., Puska, P., Blair, S. N., and Katzmarzyk, P. T. (2012). Effect of physical inactivity on major noncommunicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 380, 219–229. Leem, Y. H., Lee, Y. I., Son, H. J., and Lee, S. H. (2011). Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23. Biochem. Biophys. Res. Commun. 406, 359–365. Leonard, B., and Maes, M. (2012). Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci. Biobehav. Rev. 36, 764–785. Lepore, S. J. (1997). Expressive writing moderates the relation between intrusive thoughts and depressive symptoms. J. Pers. Soc. Psychol. 73, 1030–1037. Lewitus, G. M., Cohen, H., and Schwartz, M. (2008). Reducing


Eyre et al.

post-traumatic anxiety by immunization. Brain Behav. Immun. 22, 1108–1114. Li, Y., Xiao, B., Qiu, W., Yang, L., Hu, B., Tian, X., et al. (2010). Altered expression of CD4+CD25+ regulatory T cells and its 5-HT(1a) receptor in patients with major depression disorder. J. Affect. Disord. 124, 68–75. Libardi, C. A., De Souza, G. V., Cavaglieri, C. R., Madruga, V. A., and Chacon-Mikahil, M. P. (2012). Effect of resistance, endurance, and concurrent training on TNF-alpha, IL-6, and CRP. Med. Sci. Sports Exerc. 44, 50–56. Littrell, J. L. (2012). Taking the perspective that a depressive state reflects inflammation: implications for the use of antidepressants. Front. Psychol. 3:297. doi:10.3389/fpsyg.2012.00297 Liu, D., Wang, Z., Liu, S., Wang, F., Zhao, S., and Hao, A. (2011). Anti-inflammatory effects of fluoxetine in lipopolysaccharide(LPS)stimulated microglial cells. Neuropharmacology 61, 592–599. Lyons, A., Downer, E. J., Crotty, S., Nolan, Y. M., Mills, K. H., and Lynch, M. A. (2007). CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J. Neurosci. 27, 8309–8313. Lyons, A., McQuillan, K., Deighan, B. F., O’Reilly, J. A., Downer, E. J., Murphy, A. C., et al. (2009). Decreased neuronal CD200 expression in IL4-deficient mice results in increased neuroinflammation in response to lipopolysaccharide. Brain Behav. Immun. 23, 1020–1027. Maes, M. (2011). Depression is an inflammatory disease, but cellmediated immune activation is the key component of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 664–675. Mahendra, N., and Arkin, S. (2003). Effects of four years of exercise, language, and social interventions on Alzheimer discourse. J. Commun. Disord. 36, 395–422. Marosi, K., Bori, Z., Hart, N., Sarga, L., Koltai, E., Radak, Z., et al. (2012). Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience 226, 21–28. Martino, G., Pluchino, S., Bonfanti, L., and Schwartz, M. (2011). Brain regeneration in physiology and pathology: the immune signature driving therapeutic plasticity of neural stem cells. Physiol. Rev. 91, 1281–1304. Martins, R. A., Neves, A. P., CoelhoSilva, M. J., Verissimo, M. T., and

www.frontiersin.org


Teixeira, A. M. (2010). The effect of aerobic versus strength-based training on high-sensitivity C-reactive protein in older adults. Eur. J. Appl. Physiol. 110, 161–169. Mathieu, P., Piantanida, A. P., and Pitossi, F. (2010). Chronic expression of transforming growth factorbeta enhances adult neurogenesis. Neuroimmunomodulation 17, 200–201. Matthys, P., Mitera, T., Heremans, H., Van Damme, J., and Billiau, A. (1995). Anti-gamma interferon and anti-interleukin-6 antibodies affect staphylococcal enterotoxin B-induced weight loss, hypoglycemia, and cytokine release in D-galactosamine-sensitized and unsensitized mice. Infect. Immun. 63, 1158–1164. McAfoose, J., and Baune, B. T. (2009). Evidence for a cytokine model of cognitive function. Neurosci. Biobehav. Rev. 33, 355–366. McNally, L., Bhagwagar, Z., and Hannestad, J. (2008). Inflammation, glutamate, and glia in depression: a literature review. CNS Spectr. 13, 501–510. Mead, G. E., Morley, W., Campbell, P., Greig, C. A., McMurdo, M., and Lawlor, D. A. (2008). Exercise for depression. Cochrane Database Syst. Rev. 4, CD004366. doi: 10.1002/14651858.CD004366.pub3 Mesquita, A. R., Correia-Neves, M., Roque, S., Castro, A. G., Vieira, P., Pedrosa, J., et al. (2008). IL-10 modulates depressive-like behavior. J. Psychiatr. Res. 43, 89–97. Miller, A. H. (2010). Depression and immunity: a role for T cells? Brain Behav. Immun. 24, 1–8. Miller, A. H., Maletic, V., and Raison, C. L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741. Mitschelen, M., Yan, H., Farley, J. A., Warrington, J. P., Han, S., Herenu, C. B., et al. (2011). Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: a potential model of geriatric depression. Neuroscience 185, 50–60. Mizuhara, H., O’Neill, E., Seki, N., Ogawa, T., Kusunoki, C., Otsuka, K., et al. (1994). T cell activationassociated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6. J. Exp. Med. 179, 1529–1537. Moon, H. Y., Kim, S. H., Yang, Y. R., Song, P., Yu, H. S., Park, H. G., et al. (2012). Macrophage migration

inhibitory factor mediates the antidepressant actions of voluntary exercise. Proc. Natl. Acad. Sci. U.S.A. 109, 13094–13099. Moon, M. L., McNeil, L. K., and Freund, G. G. (2011). Macrophages make me sick: how macrophage activation states influence sickness behavior. Psychoneuroendocrinology 36, 1431–1440. Moron, J. A., Zakharova, I., Ferrer, J. V., Merrill, G. A., Hope, B., Lafer, E. M., et al. (2003). Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity. J. Neurosci. 23, 8480–8488. Moylan, S., Maes, M., Wray, N. R., and Berk, M. (2012). The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol. Psychiatry. doi: 10.1038/mp.2012.33. [Epub ahead of print]. Muller, N., Myint, A. M., and Schwarz, M. J. (2011). Inflammatory biomarkers and depression. Neurotox. Res. 19, 308–318. Musil, R., Schwarz, M. J., Riedel, M., Dehning, S., Cerovecki, A., Spellmann, I., et al. (2011). Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression – no influence of celecoxib treatment. J. Affect. Disord. 134, 217–225. Myint, A. M., Leonard, B. E., Steinbusch, H. W., and Kim, Y. K. (2005). Th1, Th2, and Th3 cytokine alterations in major depression. J. Affect. Disord. 88, 167–173. Nakajima, A., Yamada, K., Nagai, T., Uchiyama, T., Miyamoto, Y., Mamiya, T., et al. (2004). Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity. J. Neurosci. 24, 2212–2225. Nguyen, K., D’Mello, C., Le, T., Urbanski, S., and Swain, M. G. (2012). Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice. J. Hepatol. 56, 626–631. Nichol, K. E., Poon, W. W., Parachikova, A. I., Cribbs, D. H., Glabe, C. G., and Cotman, C. W. (2008). Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J. Neuroinflammation 5, 13. Nicklas, B. J., Hsu, F. C., Brinkley, T. J., Church, T., Goodpaster, B. H.,

Kritchevsky, S. B., et al. (2008). Exercise training and plasma Creactive protein and interleukin-6 in elderly people. J. Am. Geriatr. Soc. 56, 2045–2052. Nybo, L., Nielsen, B., Pedersen, B. K., Moller, K., and Secher, N. H. (2002). Interleukin-6 release from the human brain during prolonged exercise. J. Physiol. (Lond.) 542, 991–995. Ojo, B., Rezaie, P., Gabbott, P. L., Davies, H., Colyer, F., Cowley, T. R., et al. (2012). Age-related changes in the hippocampus (loss of synaptophysin and glial-synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL. Brain Behav. Immun. 26, 778–788. Olah, M., Ping, G., De Haas, A. H., Brouwer, N., Meerlo, P., Van Der Zee, E. A., et al. (2009). Enhanced hippocampal neurogenesis in the absence of microglia T cell interaction and microglia activation in the murine running wheel model. Glia 57, 1046–1061. Park, S. E., Dantzer, R., Kelley, K. W., and McCusker, R. H. (2011a). Central administration of insulinlike growth factor-I decreases depressive-like behavior and brain cytokine expression in mice. J. Neuroinflammation 8, 12. Park, S. E., Lawson, M., Dantzer, R., Kelley, K. W., and McCusker, R. H. (2011b). Insulin-like growth factor-I peptides act centrally to decrease depression-like behavior of mice treated intraperitoneally with lipopolysaccharide. J. Neuroinflammation 8, 179. Pasco, J. A., Jacka, F. N., Williams, L. J., Brennan, S. L., Leslie, E., and Berk, M. (2011a). Don’t worry, be active: positive affect and habitual physical activity. Aust. N. Z. J. Psychiatry 45, 1047–1052. Pasco, J. A., Williams, L. J., Jacka, F. N., Henry, M. J., Coulson, C. E., Brennan, S. L., et al. (2011b). Habitual physical activity and the risk for depressive and anxiety disorders among older men and women. Int. Psychogeriatr. 23, 292–298. Pereira, A. C., Huddleston, D. E., Brickman, A. M., Sosunov, A. A., Hen, R., McKhann, G. M., et al. (2007). An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc. Natl. Acad. Sci. U.S.A. 104, 5638–5643. Ponomarev, E. D., Veremeyko, T., and Weiner, H. L. (2012). MicroRNAs are universal regulators of differentiation, activation, and polarization of microglia and macrophages in


Eyre et al.

normal and diseased CNS. Glia 61, 91–103. Popoli, M., Yan, Z., McEwen, B. S., and Sanacora, G. (2012). The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 22–37. Prinz, M., Priller, J., Sisodia, S. S., and Ransohoff, R. M. (2011). Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235. Quan, N., and Banks, W. A. (2007). Brain-immune communication pathways. Brain Behav. Immun. 21, 727–735. Raison, C. L., and Miller, A. H. (2011). Is depression an inflammatory disorder? Curr. Psychiatry Rep. 13, 467–475. Raison, C. L., Rutherford, R. E., Woolwine, B. J., Shuo, C., Schettler, P., Drake, D. F., et al. (2012). A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. Arch. Gen. Psychiatry. doi: 10.1001/2013.jamapsychiatry.4. [Epub ahead of print]. Ransohoff, R. M., Kivisakk, P., and Kidd, G. (2003). Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 3, 569–581. Rasmussen, P., Vedel, J. C., Olesen, J., Adser, H., Pedersen, M. V., Hart, E., et al. (2011). In humans IL-6 is released from the brain during and after exercise and paralleled by enhanced IL-6 mRNA expression in the hippocampus of mice. Acta Physiol. (Oxf.) 201, 475–482. Rethorst, C. D., Moynihan, J., Lyness, J. M., Heffner, K. L., and Chapman, B. P. (2011). Moderating effects of moderate-intensity physical activity in the relationship between depressive symptoms and interleukin-6 in primary care patients. Psychosom. Med. 73, 265–269. Rethorst, C. D., Toups, M. S., Greer, T. L., Nakonezny, P. A., Carmody, T. J., Grannemann, B. D., et al. (2012). Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder. Mol. Psychiatry. doi: 10.1038/mp.2012.125. [Epub ahead of print]. Rethorst, C. D., Wipfli, B. M., and Landers, D. M. (2009). The antidepressive effects of exercise: a metaanalysis of randomized trials. Sports Med. 39, 491–511. Reuben, D. B., Judd-Hamilton, L., Harris, T. B., and Seeman, T. E. (2003). The associations between physical


activity and inflammatory markers in high-functioning older persons: MacArthur Studies of Successful Aging. J. Am. Geriatr. Soc. 51, 1125–1130. Rimer, J., Dwan, K., Lawlor, D. A., Greig, C. A., McMurdo, M., Morley, W., et al. (2012). Exercise for depression. Cochrane Database Syst. Rev. 7, CD004366. Rogers, J. T., Morganti, J. M., Bachstetter, A. D., Hudson, C. E., Peters, M. M., Grimmig, B. A., et al. (2011). CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J. Neurosci. 31, 16241–16250. Rolls, A., Schori, H., London, A., and Schwartz, M. (2008). Decrease in hippocampal neurogenesis during pregnancy: a link to immunity. Mol. Psychiatry 13, 468–469. Ron-Harel, N., Cardon, M., and Schwartz, M. (2011). Brain homeostasis is maintained by “danger” signals stimulating a supportive immune response within the brain’s borders. Brain Behav. Immun. 25, 1036–1043. Rook, G. A., Lowry, C. A., and Raison, C. L. (2011). Lymphocytes in neuroprotection, cognition and emotion: is intolerance really the answer? Brain Behav. Immun. 25, 591–601. Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., et al. (2006a). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR∗D report. Am. J. Psychiatry 163, 1905–1917. Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Stewart, J. W., Nierenberg, A. A., Thase, M. E., et al. (2006b). Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N. Engl. J. Med. 354, 1231–1242. Salmon, P. (2001). Effects of physical exercise on anxiety, depression, and sensitivity to stress: a unifying theory. Clin. Psychol. Rev. 21, 33–61. Santello, M., and Volterra, A. (2012). TNFalpha in synaptic function: switching gears. Trends Neurosci. 35, 638–647. Santos, R. V., Viana, V. A., Boscolo, R. A., Marques, V. G., Santana, M. G., Lira, F. S., et al. (2012). Moderate exercise training modulates cytokine profile and sleep in elderly people. Cytokine 60, 731–735. Sarris, J., Moylan, S., Camfield, D. A., Pase, M. P., Mischoulon, D., Berk, M., et al. (2012). Complementary medicine, exercise, meditation, diet, and


lifestyle modification for anxiety disorders: a review of current evidence. Evid. Based Complement. Alternat. Med. 2012, 809653. Schwartz, M., Butovsky, O., Bruck, W., and Hanisch, U. K. (2006). Microglial phenotype: is the commitment reversible? Trends Neurosci. 29, 68–74. Schwartz, M., and Shechter, R. (2010a). Protective autoimmunity functions by intracranial immunosurveillance to support the mind: the missing link between health and disease. Mol. Psychiatry 15, 342–354. Schwartz, M., and Shechter, R. (2010b). Systemic inflammatory cells fight off neurodegenerative disease. Nat. Rev. Neurol. 6, 405–410. Schwarz, J. M., and Bilbo, S. D. (2011). “The immune system and the developing brain,” in Colloquium Series on the Developing Brain, Vol. 2, No. 3, ed. M. M. McCarthy (San Rafael: Morgan and Claypool Publishers), 1–128. Schwarz, J. M., and Bilbo, S. D. (2012). Sex, glia, and development: interactions in health and disease. Horm. Behav. 62, 243–253. Shaked, I., Tchoresh, D., Gersner, R., Meiri, G., Mordechai, S., Xiao, X., et al. (2005). Protective autoimmunity: interferon-gamma enables microglia to remove glutamate without evoking inflammatory mediators. J. Neurochem. 92, 997–1009. Shechter, R., London, A., Varol, C., Raposo, C., Cusimano, M., Yovel, G., et al. (2009). Infiltrating bloodderived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6:e1000113. doi:10.1371/journal.pmed.1000113 Sherry, C. L., Kim, S. S., Dilger, R. N., Bauer, L. L., Moon, M. L., Tapping, R. I., et al. (2010). Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL4 and Th2 polarization. Brain Behav. Immun. 24, 631–640. Shimizu, E., Kawahara, K., Kajizono, M., Sawada, M., and Nakayama, H. (2008). IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1–42) by rat primary type 2 microglia. J. Immunol. 181, 6503–6513. Sigwalt, A. R., Budde, H., Helmich, I., Glaser, V., Ghisoni, K., Lanza, S., et al. (2011). Molecular aspects involved in swimming exercise training reducing anhedonia in a rat model of depression. Neuroscience 192, 661–674.

Smith, P. J., Blumenthal, J. A., Hoffman, B. M., Cooper, H., Strauman, T. A., Welsh-Bohmer, K., et al. (2010). Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom. Med. 72, 239–252. Southwick, S. M., and Charney, D. S. (2012). The science of resilience: implications for the prevention and treatment of depression. Science 338, 79–82. Starkie, R., Ostrowski, S. R., Jauffred, S., Febbraio, M., and Pedersen, B. K. (2003). Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 17, 884–886. Stellwagen, D., and Malenka, R. C. (2006). Synaptic scaling mediated by glial TNF-alpha. Nature 440, 1054–1059. Stewart, L. K., Flynn, M. G., Campbell, W. W., Craig, B. A., Robinson, J. P., Timmerman, K. L., et al. (2007). The influence of exercise training on inflammatory cytokines and Creactive protein. Med. Sci. Sports Exerc. 39, 1714–1719. Stuart, M. J., and Baune, B. T. (2012). Depression and type 2 diabetes: inflammatory mechanisms of a psychoneuroendocrine comorbidity. Neurosci. Biobehav. Rev. 36, 658–676. Sutcigil, L., Oktenli, C., Musabak, U., Bozkurt, A., Cansever, A., Uzun, O., et al. (2007). Pro- and antiinflammatory cytokine balance in major depression: effect of sertraline therapy. Clin. Dev. Immunol. 2007, 76396. Trejo, J. L., Piriz, J., Llorens-Martin, M. V., Fernandez, A. M., Bolos, M., Leroith, D., et al. (2007). Central actions of liver-derived insulin-like growth factor I underlying its procognitive effects. Mol. Psychiatry 12, 1118–1128. Trivedi, M. H., Greer, T. L., Church, T. S., Carmody, T. J., Grannemann, B. D., Galper, D. I., et al. (2011). Exercise as an augmentation treatment for nonremitted major depressive disorder: a randomized, parallel dose comparison. J. Clin. Psychiatry 72, 677–684. Trivedi, M. H., Rush, A. J., Wisniewski, S. R., Nierenberg, A. A., Warden, D., Ritz, L., et al. (2006). Evaluation of outcomes with citalopram for depression using measurementbased care in STAR∗D: implications for clinical practice. Am. J. Psychiatry 163, 28–40. Tse, H. M., Milton, M. J., Schreiner, S., Profozich, J. L., Trucco, M., and Piganelli, J. D. (2007). Disruption of


Eyre et al.

innate-mediated proinflammatory cytokine and reactive oxygen species third signal leads to antigen-specific hyporesponsiveness. J. Immunol. 178, 908–917. Vukovic, J., Colditz, M. J., Blackmore, D. G., Ruitenberg, M. J., and Bartlett, P. F. (2012). Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J. Neurosci. 32, 6435–6443. Walker, F. R. (2012). A review of the mechanism of action for selective serotonin reuptake inhibitors: do these drugs possess antiinflammatory properties and is this relevant in the treatment of depression? Neuropharmacology 67C, 304–317. Walker, P. A., Letourneau, P. A., Bedi, S., Shah, S. K., Jimenez, F., and Cox, C. S. Jr (2011). Progenitor cells as remote “bioreactors”: neuroprotection via modulation of the systemic inflammatory response. World J. Stem Cells 3, 9–18. Walsh, J. T., and Kipnis, J. (2011). Regulatory T cells in CNS injury: the simple, the complex and the confused. Trends. Mol. Med. 17, 541–547.

www.frontiersin.org


Walton, N. M., Sutter, B. M., Laywell, E. D., Levkoff, L. H., Kearns, S. M., Marshall, G. P. II, et al. (2006). Microglia instruct subventricular zone neurogenesis. Glia 54, 815–825. Warner-Schmidt, J. L., Vanover, K. E., Chen, E. Y., Marshall, J. J., and Greengard, P. (2011). Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc. Natl. Acad. Sci. U.S.A. 108, 9262–9267. WHO. (2008). Global Burden of Disease: 2004 Update. Geneva: WHO. Wong, M. L., Dong, C., Maestre-Mesa, J., and Licinio, J. (2008). Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol. Psychiatry 13, 800–812. Wu, M. D., Hein, A. M., Moravan, M. J., Shaftel, S. S., Olschowka, J. A., and O’Banion, M. K. (2012). Adult murine hippocampal neurogenesis is inhibited by sustained IL1beta and not rescued by voluntary

running. Brain Behav. Immun. 26, 292–300. Yi, C. X., Al-Massadi, O., Donelan, E., Lehti, M., Weber, J., Ress, C., et al. (2012). Exercise protects against high-fat diet-induced hypothalamic inflammation. Physiol. Behav. 106, 485–490. Yirmiya, R., and Goshen, I. (2011). Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav. Immun. 25, 181–213. Zhou, X., Bailey-Bucktrout, S., Jeker, L. T., and Bluestone, J. A. (2009). Plasticity of CD4+ FoxP3+ T cells. Curr. Opin. Immunol. 21, 281–285. Zhu, C. B., Blakely, R. D., and Hewlett, W. A. (2006). The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 31, 2121–2131. Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., et al. (2006). Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9, 268–275.

Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received: 30 November 2012; paper pending published: 25 December 2012; accepted: 07 January 2013; published online: 04 February 2013. Citation: Eyre HA, Papps E and Baune BT (2013) Treating depression and depression-like behavior with physical activity: an immune perspective. Front. Psychiatry 4:3. doi: 10.3389/fpsyt.2013.00003 This article was submitted to Frontiers in Affective Disorders and Psychosomatic Research, a specialty of Frontiers in Psychiatry. Copyright © 2013 Eyre, Papps and Baune. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.


ORIGINAL RESEARCH ARTICLE

PSYCHIATRY

published: 02 April 2013 doi: 10.3389/fpsyt.2013.00022

Recreational physical activity ameliorates some of the negative impact of major depression on health-related quality of life Scott B. Patten 1,2,3 *, Jeanne V. A. Williams 1 , Dina H. Lavorato 1 and Andrew G. M. Bulloch 1,2,3 1 2 3

Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada Department of Psychiatry, University of Calgary, Calgary, AB, Canada Mathison Center for Research and Education in Mental Health, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

Edited by: Eduardo Lusa Cadore, Federal University of Rio Grande do Sul, Brazil Reviewed by: Mauro Giovanni Carta, University of Cagliari, Italy Alexandra Latini, Universidade Federal de Santa Catarina, Brazil *Correspondence: Scott B. Patten, Department of Community Health Sciences, University of Calgary, 3rd Floor TRW Building, 3280 Hospital Drive N.W., Calgary, AB T2N4Z6, Canada. e-mail: [email protected]

Background: Major depressive episodes have a negative effect on health-related quality of life (HRQoL). The objective of this study was to determine whether recreational physical activity can ameliorate some of this negative impact. Methods: The data source for the study was the Canadian National Population Health Survey (NPHS). The NPHS is a longitudinal study that has collected data from a representative cohort of 15,254 community residents. Sixteen years of follow-up data are available. The NPHS included: an instrument to assess MDE (the Composite International Diagnostic Interview Short Form for Major Depression), an inventory of recreational activities (each associated with hours of participation and estimated metabolic expenditures), and a HRQoL instrument (the Health Utility Index, Mark 3, or HUI3). Proportional hazard and linear regression models were used in this study to determine whether MDE-related declines in HRQoL were lessened by participation in an active recreational lifestyle. Results: Consistent with expectation, major depression was associated with a significant decline in HRQoL over time. While no statistical interactions were observed, the risk of diminished HRQoL in association with MDE was reduced by physical activity. In a proportional hazards model, the hazard ratio for transition to poor HRQoL was 0.7 (95% CI: 0.6–0.8, p < 0.0001). In linear regression models, physical activity was significantly associated with more positive HRQoL (β = 0.019, 95% CI 0.004 to −0.034, p = 0.02). Conclusion: Recreational physical activity appears to ameliorate some of the decline in HRQoL seen in association with MDE. Physical activity may be an effective tertiary preventive strategy for this condition. Keywords: depressive disorders, quality of life, physical activity, recreation, epidemiologic studies, longitudinal studies

INTRODUCTION Depressive disorders are among the most important contributors to disease burden in developed countries (World Health Organization, 2001; Wittchen et al., 2011). These disorders affect mortality (Wulsin et al., 1999; Lawrence et al., 2010; Patten et al., 2011), but their main impact is through diminished functioning and lower health-related quality of life (HRQoL). The most important depressive disorder, Major Depressive Disorder has an annual prevalence in North America of approximately 5% (Kessler et al., 2003; Patten et al., 2006). As these conditions are so common, effective strategies to reduce their impact will have a substantially positive effect on HRQoL at the population level. Physical activity is a candidate strategy. It is not difficult to identify mechanisms by which physical activity may have a positive impact on outcomes of depressive disorders. Depressive disorders increase the risks of a variety of chronic physical conditions such as hypertension (Patten et al., 2009), diabetes (Brown et al., 2005), and heart disease (Gilmour,

2008). Physical activity may help to ameliorate these risks. Physical activity may also counteract negative dynamics that can perpetuate depression, such as the emergence of a lifestyle that is lacking in rewarding or enjoyable activity (Hopko et al., 2003). A growing literature has examined the role of exercise in treatment of depression. The clinical trial literature has been summarized in a recent Cochrane Review (Rimer et al., 2012). Only a few studies have examined quality of life as an outcome. Carta et al. reported that the physical subscale of the WHOQOL-Bref improved in a randomized trial among subjects receiving antidepressant treatment and adjunctive exercise, whereas this did not occur in a control group receiving only antidepressant treatment (Carta et al., 2008). Singh et al. also examined quality of life outcomes in a trial of highintensity progressive resistance training in community dwelling adults >60 years old. Improvements were noted in several Medical Outcomes Study Short Form (SF-36) subscales, although only one of these, vitality, achieved statistical significance (Singh et al., 2005).


April 2013 | Volume 4 | Article 22 | 38

Patten et al.

To our knowledge, no epidemiologic studies have examined the joint effects of physical activity and major depressive episode (MDE) on quality of life outcomes in major depression. The objective of this study was to examine these effects using a representative general population sample.

MATERIALS AND METHODS The data source for this study was a Canadian prospective cohort study called the National Population Health Survey (NPHS) (Swain et al., 1999). This is a longitudinal study based on a nationally representative community sample assembled by Statistics Canada (Canada’s national statistical agency) in 1994/1995. Baseline interviews (mostly face to face) were carried out in 1994 and participants were re-interviewed every 2 years subsequently, usually by telephone. Statistics Canada reported a 69.7% rate of successful follow-up at completion of the project in 2010 (Statistics Canada, 2012). The original NPHS longitudinal cohort included 17,276 participants in total, but the current analysis was restricted to 15,254 respondents who were over the age of 12 at the time of the initial 1994 interview. This subset was further restricted in specific analyses depending on the health transitions of interest to the study. For example, in the component of the analysis concerned with incidence of low HRQoL, those already having low HRQoL at the time of the baseline interview were excluded because they could not be considered at risk of developing this outcome. The NPHS interview included the Composite International Diagnostic Interview Short Form (CIDI-SF) (Kessler et al., 1998) for Major Depression. This is a brief structured interview designed to identify people with a high probability of past year MDE. The CIDI-SF was developed using data from the National Comorbidity Survey in the US (Kessler et al., 1994), which used the DSM-IIIR classification. The instrument consists of a modified subset of CIDI items and is scored using a predictive algorithm. For the current analysis, the 90% predictive cut-point was used. This scoring procedure requires endorsement of five symptom-based criteria (at least one of which must be depressed mood or loss of interest), providing face validity for the DSM-IV definition of MDE. Each cycle of the NPHS also included items assessing participation in 21 recreational physical activities. Each activity was assigned a metabolic indicator (MET) value (Statistics Canada, 2004) representing an estimated metabolic energy cost (in kilocalories expended per kilogram of body weight per hour) which is expressed as a multiple of the resting metabolic rate. For example, the MET value for playing basketball is six, indicating that people playing basketball expend an estimated six times more energy per hour than people at rest. Daily estimated energy expenditure was then calculated from MET values based on the amount of time spent participating in each specified activity. A total estimated energy expenditure of 1.5 kcal/kg/day was used to categorize respondents into active or inactive categories. This level of activity corresponds approximately to 30 min of walking for exercise per day. The methodological approach to the assessment of leisure time physical activity was developed by the Canadian Fitness and Lifestyle Institute1 . 1 http://www.cflri.ca

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Depression, physical activity, and quality of life

Health-related quality of life was assessed in the NPHS using the Health Utility Index, Mark 3 (HUI3). The Health Utilities Index (HUI) is a system for measuring HRQoL and for producing preference-weighted health utilities. The HUI3 system was originally developed for the 1990 Ontario Health Survey (Horsman et al., 2003). The HUI covers eight attributes: vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain. Each level of each attribute is associated with an attribute-specific utility score with values ranging from 1.0 (the highest of the five or six options) to zero (the lowest). However, most commonly, the various health states are used to compute a multi-attribute score using a multiplicative multi-attribute algorithm (Feeny et al., 2002). The preference weights used in this algorithm derive from data collected in a survey employing standard gamble methods (Feeny et al., 2002). In the version used by Statistics Canada, perfect HRQoL is associated with an HUI3 score of 1.0, a state equivalent to death is assigned a score of zero and health states of less than zero are viewed as being worse than death. Additional information is available at the instrument’s website2 . Various questionnaires that provide sufficient information to describe health status have been developed for use with the HUI3. The version used by Statistics Canada refers to “usual” experience of various impairments (some other versions use past month or past week ratings). The instrument used by Statistics Canada in its national surveys is called the Comprehensive Health Status Measurement System (CHSMS). This instrument was included in the NPHS. Eight domains are covered by the CHSMS: vision, hearing, speech, mobility, dexterity, emotion, cognition. As noted above, each of the individual health states is assessed at several different levels, which leads to 972,000 possible unique health states, each of which is associated with a HRQoL value. We were interested in examining associations between major depression, physical activity, and HRQoL from several different perspectives. A commonly employed interpretation of HUI3 data is a nominal one, with scores

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